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1. Whole-genome association analysis of treatment response in obsessive-compulsive disorder.

Author: Qin, H, Samuels, JF, Wang, Y, Zhu, Y, Grados, MA, Riddle, MA, Greenberg, BD, Knowles, JA, Fyer, AJ, McCracken, JT, Murphy, DL, Rasmussen, SA, Cullen, BA, Piacentini, J, Geller, D, Stewart, SE, Pauls, D, Bienvenu, OJ, Goes, FS, Maher, B, Pulver, AE, Valle, D, Lange, C, Mattheisen, M, McLaughlin, NC, Liang, K-Y, Nurmi, EL, Askland, KD, Nestadt, G, and Shugart, YY
Subjects: Humans, Genetic Predisposition to Disease, Membrane Proteins, Serotonin Uptake Inhibitors, Treatment Outcome, Obsessive-Compulsive Disorder, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Adolescent, Adult, Aged, Middle Aged, Child, Female, Male, Genetic Variation, Genome-Wide Association Study, Self Report, Polymorphism, Single Nucleotide, Psychiatry, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences
Abstract: Up to 30% of patients with obsessive-compulsive disorder (OCD) exhibit an inadequate response to serotonin reuptake inhibitors (SRIs). To date, genetic predictors of OCD treatment response have not been systematically investigated using genome-wide association study (GWAS). To identify specific genetic variations potentially influencing SRI response, we conducted a GWAS study in 804 OCD patients with information on SRI response. SRI response was classified as 'response' (n=514) or 'non-response' (n=290), based on self-report. We used the more powerful Quasi-Likelihood Score Test (the MQLS test) to conduct a genome-wide association test correcting for relatedness, and then used an adjusted logistic model to evaluate the effect size of the variants in probands. The top single-nucleotide polymorphism (SNP) was rs17162912 (P=1.76 × 10(-8)), which is near the DISP1 gene on 1q41-q42, a microdeletion region implicated in neurological development. The other six SNPs showing suggestive evidence of association (P
Published: 2016

2. Genome-wide association study in obsessive-compulsive disorder: results from the OCGAS.

Author: Mattheisen, M, Samuels, JF, Wang, Y, Greenberg, BD, Fyer, AJ, McCracken, JT, Geller, DA, Murphy, DL, Knowles, JA, Grados, MA, Riddle, MA, Rasmussen, SA, McLaughlin, NC, Nurmi, EL, Askland, KD, Qin, H-D, Cullen, BA, Piacentini, J, Pauls, DL, Bienvenu, OJ, Stewart, SE, Liang, K-Y, Goes, FS, Maher, B, Pulver, AE, Shugart, YY, Valle, D, Lange, C, and Nestadt, G
Subjects: Chromosomes, Human, Pair 9, Humans, Genetic Predisposition to Disease, Oligonucleotide Array Sequence Analysis, Follow-Up Studies, Gene Expression Profiling, Cooperative Behavior, Obsessive-Compulsive Disorder, Genotype, Polymorphism, Single Nucleotide, Adult, Family Health, Female, Male, Receptor-Like Protein Tyrosine Phosphatases, Class 2, Genome-Wide Association Study, Young Adult, Genetics, Human Genome, Mental Health, Clinical Research, Aetiology, 2.1 Biological and endogenous factors, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract: Obsessive-compulsive disorder (OCD) is a psychiatric condition characterized by intrusive thoughts and urges and repetitive, intentional behaviors that cause significant distress and impair functioning. The OCD Collaborative Genetics Association Study (OCGAS) is comprised of comprehensively assessed OCD patients with an early age of OCD onset. After application of a stringent quality control protocol, a total of 1065 families (containing 1406 patients with OCD), combined with population-based samples (resulting in a total sample of 5061 individuals), were studied. An integrative analyses pipeline was utilized, involving association testing at single-nucleotide polymorphism (SNP) and gene levels (via a hybrid approach that allowed for combined analyses of the family- and population-based data). The smallest P-value was observed for a marker on chromosome 9 (near PTPRD, P=4.13 × 10(-)(7)). Pre-synaptic PTPRD promotes the differentiation of glutamatergic synapses and interacts with SLITRK3. Together, both proteins selectively regulate the development of inhibitory GABAergic synapses. Although no SNPs were identified as associated with OCD at genome-wide significance level, follow-up analyses of genome-wide association study (GWAS) signals from a previously published OCD study identified significant enrichment (P=0.0176). Secondary analyses of high-confidence interaction partners of DLGAP1 and GRIK2 (both showing evidence for association in our follow-up and the original GWAS study) revealed a trend of association (P=0.075) for a set of genes such as NEUROD6, SV2A, GRIA4, SLC1A2 and PTPRD. Analyses at the gene level revealed association of IQCK and C16orf88 (both P
Published: 2015

3. Combining schizophrenia and depression polygenic risk scores improves the genetic prediction of lithium response in bipolar disorder patients (vol 12, 278, 2022)

Author: Schubert, KO, Thalamuthu, A, Amare, AT, Frank, J, Streit, F, Adl, M, Akula, N, Akiyama, K, Ardau, R, Arias, B, Aubry, J-M, Backlund, L, Bhattacharjee, AK, Bellivier, F, Benabarre, A, Bengesser, S, Biernacka, JM, Birner, A, Marie-Claire, C, Cearns, M, Cervantes, P, Chen, H-C, Chillotti, C, Cichon, S, Clark, SR, Cruceanu, C, Czerski, PM, Dalkner, N, Dayer, A, Degenhardt, F, Del Zompo, M, DePaulo, JR, Etain, B, Falkai, P, Forstner, AJ, Frisen, L, Frye, MA, Fullerton, JM, Gard, S, Garnham, JS, Goes, FS, Grigoroiu-Serbanescu, M, Grof, P, Hashimoto, R, Hauser, J, Heilbronner, U, Herms, S, Hoffmann, P, Hou, L, Hsu, Y-H, Jamain, S, Jimenez, E, Kahn, J-P, Kassem, L, Kuo, P-H, Kato, T, Kelsoe, J, Kittel-Schneider, S, Ferensztajn-Rochowiak, E, Konig, B, Kusumi, I, Laje, G, Landen, M, Lavebratt, C, Leboyer, M, Leckband, SG, Maj, M, Manchia, M, Martinsson, L, McCarthy, MJ, McElroy, S, Colom, F, Mitjans, M, Mondimore, FM, Monteleone, P, Nievergelt, CM, Nothen, MM, Novak, T, O'Donovan, C, Ozaki, N, Osby, U, Papiol, S, Pfennig, A, Pisanu, C, Potash, JB, Reif, A, Reininghaus, E, Rouleau, GA, Rybakowski, JK, Schalling, M, Schofield, PR, Schweizer, BW, Severino, G, Shekhtman, T, Shilling, PD, Shimoda, K, Simhandl, C, Slaney, CM, Squassina, A, Stamm, T, Stopkova, P, Tekola-Ayele, F, Tortorella, A, Turecki, G, Veeh, J, Vieta, E, Witt, SH, Roberts, G, Zandi, PP, Alda, M, Bauer, M, McMahon, FJ, Mitchell, PB, Schulze, TG, Rietschel, M, Baune, BT, Schubert, KO, Thalamuthu, A, Amare, AT, Frank, J, Streit, F, Adl, M, Akula, N, Akiyama, K, Ardau, R, Arias, B, Aubry, J-M, Backlund, L, Bhattacharjee, AK, Bellivier, F, Benabarre, A, Bengesser, S, Biernacka, JM, Birner, A, Marie-Claire, C, Cearns, M, Cervantes, P, Chen, H-C, Chillotti, C, Cichon, S, Clark, SR, Cruceanu, C, Czerski, PM, Dalkner, N, Dayer, A, Degenhardt, F, Del Zompo, M, DePaulo, JR, Etain, B, Falkai, P, Forstner, AJ, Frisen, L, Frye, MA, Fullerton, JM, Gard, S, Garnham, JS, Goes, FS, Grigoroiu-Serbanescu, M, Grof, P, Hashimoto, R, Hauser, J, Heilbronner, U, Herms, S, Hoffmann, P, Hou, L, Hsu, Y-H, Jamain, S, Jimenez, E, Kahn, J-P, Kassem, L, Kuo, P-H, Kato, T, Kelsoe, J, Kittel-Schneider, S, Ferensztajn-Rochowiak, E, Konig, B, Kusumi, I, Laje, G, Landen, M, Lavebratt, C, Leboyer, M, Leckband, SG, Maj, M, Manchia, M, Martinsson, L, McCarthy, MJ, McElroy, S, Colom, F, Mitjans, M, Mondimore, FM, Monteleone, P, Nievergelt, CM, Nothen, MM, Novak, T, O'Donovan, C, Ozaki, N, Osby, U, Papiol, S, Pfennig, A, Pisanu, C, Potash, JB, Reif, A, Reininghaus, E, Rouleau, GA, Rybakowski, JK, Schalling, M, Schofield, PR, Schweizer, BW, Severino, G, Shekhtman, T, Shilling, PD, Shimoda, K, Simhandl, C, Slaney, CM, Squassina, A, Stamm, T, Stopkova, P, Tekola-Ayele, F, Tortorella, A, Turecki, G, Veeh, J, Vieta, E, Witt, SH, Roberts, G, Zandi, PP, Alda, M, Bauer, M, McMahon, FJ, Mitchell, PB, Schulze, TG, Rietschel, M, and Baune, BT
Published: 2022

4. Genome-wide association study of pediatric obsessive-compulsive traits: shared genetic risk between traits and disorder

Author: Burton, CL, Lemire, M, Xiao, B, Corfield, EC, Erdman, L, Bralten, J, Poelmans, G, Yu, D, Shaheen, SM, Goodale, T, Sinopoli, VM, Askland, KD, Barlassina, C, Bienvenu, OJ, Black, D, Bloch, M, Brentani, H, Camarena, B, Cappi, C, Cath, D, Cavallini, MC, Ciullo, V, Conti, D, Cook, EH, Coric, V, Cullen, BA, Cusi, D, Davis, LK, Delorme, R, Denys, D, Derks, E, Eapen, V, Edlund, C, Falkai, P, Fyer, AJ, Geller, DA, Goes, FS, Grabe, HJ, Grados, MA, Greenberg, BD, Grünblatt, E, Guo, W, Hounie, AG, Jenike, M, Keenan, CL, Kennedy, JL, Khramtsova, EA, Knowles, JA, Krasnow, J, Lange, C, Lanzagorta, N, Leboyer, M, Liang, KY, Lochner, C, Macciardi, F, Maher, B, Mathews, CA, Mattheisen, M, McCracken, JT, McGregor, N, McLaughlin, NCR, Miguel, EC, Neale, B, Nestadt, G, Nestadt, PS, Nicolini, H, Nurmi, EL, Osiecki, L, Piacentini, J, Pittenger, C, Posthuma, D, Pulver, AE, Rasmussen, SA, Rauch, S, Richter, MA, Riddle, MA, Ripke, S, Ruhrmann, S, Sampaio, AS, Samuels, JF, Scharf, JM, Shugart, YY, Smit, JH, Stein, DJ, Stewart, SE, Turiel, M, Vallada, H, Veenstra-VanderWeele, J, Vulink, N, Wagner, M, Walitza, S, Wang, Y, Wendland, J, Zai, G, Soreni, N, Hanna, GL, Fitzgerald, KD, Rosenberg, D, Paterson, AD, Burton, CL, Lemire, M, Xiao, B, Corfield, EC, Erdman, L, Bralten, J, Poelmans, G, Yu, D, Shaheen, SM, Goodale, T, Sinopoli, VM, Askland, KD, Barlassina, C, Bienvenu, OJ, Black, D, Bloch, M, Brentani, H, Camarena, B, Cappi, C, Cath, D, Cavallini, MC, Ciullo, V, Conti, D, Cook, EH, Coric, V, Cullen, BA, Cusi, D, Davis, LK, Delorme, R, Denys, D, Derks, E, Eapen, V, Edlund, C, Falkai, P, Fyer, AJ, Geller, DA, Goes, FS, Grabe, HJ, Grados, MA, Greenberg, BD, Grünblatt, E, Guo, W, Hounie, AG, Jenike, M, Keenan, CL, Kennedy, JL, Khramtsova, EA, Knowles, JA, Krasnow, J, Lange, C, Lanzagorta, N, Leboyer, M, Liang, KY, Lochner, C, Macciardi, F, Maher, B, Mathews, CA, Mattheisen, M, McCracken, JT, McGregor, N, McLaughlin, NCR, Miguel, EC, Neale, B, Nestadt, G, Nestadt, PS, Nicolini, H, Nurmi, EL, Osiecki, L, Piacentini, J, Pittenger, C, Posthuma, D, Pulver, AE, Rasmussen, SA, Rauch, S, Richter, MA, Riddle, MA, Ripke, S, Ruhrmann, S, Sampaio, AS, Samuels, JF, Scharf, JM, Shugart, YY, Smit, JH, Stein, DJ, Stewart, SE, Turiel, M, Vallada, H, Veenstra-VanderWeele, J, Vulink, N, Wagner, M, Walitza, S, Wang, Y, Wendland, J, Zai, G, Soreni, N, Hanna, GL, Fitzgerald, KD, Rosenberg, D, and Paterson, AD
Abstract: Using a novel trait-based measure, we examined genetic variants associated with obsessive-compulsive (OC) traits and tested whether OC traits and obsessive-compulsive disorder (OCD) shared genetic risk. We conducted a genome-wide association analysis (GWAS) of OC traits using the Toronto Obsessive-Compulsive Scale (TOCS) in 5018 unrelated Caucasian children and adolescents from the community (Spit for Science sample). We tested the hypothesis that genetic variants associated with OC traits from the community would be associated with clinical OCD using a meta-analysis of all currently available OCD cases. Shared genetic risk was examined between OC traits and OCD in the respective samples using polygenic risk score and genetic correlation analyses. A locus tagged by rs7856850 in an intron of PTPRD (protein tyrosine phosphatase δ) was significantly associated with OC traits at the genome-wide significance level (p = 2.48 × 10−8). rs7856850 was also associated with OCD in a meta-analysis of OCD case/control genome-wide datasets (p = 0.0069). The direction of effect was the same as in the community sample. Polygenic risk scores from OC traits were significantly associated with OCD in case/control datasets and vice versa (p’s < 0.01). OC traits were highly, but not significantly, genetically correlated with OCD (rg = 0.71, p = 0.062). We report the first validated genome-wide significant variant for OC traits in PTPRD, downstream of the most significant locus in a previous OCD GWAS. OC traits measured in the community sample shared genetic risk with OCD case/control status. Our results demonstrate the feasibility and power of using trait-based approaches in community samples for genetic discovery.
Published: 2021

5. HLA-DRB1 and HLA-DQB1 genetic diversity modulates response to lithium in bipolar affective disorders

Author: Le Clerc, S, Lombardi, L, Baune, BT, Amare, AT, Schubert, KO, Hou, L, Clark, SR, Papiol, S, Cearns, M, Heilbronner, U, Degenhardt, F, Tekola-Ayele, F, Hsu, YH, Shekhtman, T, Adli, M, Akula, N, Akiyama, K, Ardau, R, Arias, B, Aubry, JM, Backlund, L, Bhattacharjee, AK, Bellivier, F, Benabarre, A, Bengesser, S, Biernacka, JM, Birner, A, Brichant-Petitjean, C, Cervantes, P, Chen, HC, Chillotti, C, Cichon, S, Cruceanu, C, Czerski, PM, Dalkner, N, Dayer, A, Del Zompo, M, DePaulo, JR, Étain, B, Jamain, S, Falkai, P, Forstner, AJ, Frisen, L, Frye, MA, Fullerton, JM, Gard, S, Garnham, JS, Goes, FS, Grigoroiu-Serbanescu, M, Grof, P, Hashimoto, R, Hauser, J, Herms, S, Hoffmann, P, Jiménez, E, Kahn, JP, Kassem, L, Kuo, PH, Kato, T, Kelsoe, JR, Kittel-Schneider, S, Ferensztajn-Rochowiak, E, König, B, Kusumi, I, Laje, G, Landén, M, Lavebratt, C, Leckband, SG, Tortorella, A, Manchia, M, Martinsson, L, McCarthy, MJ, McElroy, SL, Colom, F, Millischer, V, Mitjans, M, Mondimore, FM, Monteleone, P, Nievergelt, CM, Nöthen, MM, Novák, T, O’Donovan, C, Ozaki, N, Ösby, U, Pfennig, A, Potash, JB, Reif, A, Reininghaus, E, Rouleau, GA, Rybakowski, JK, Schalling, M, Schofield, PR, Schweizer, BW, Severino, G, Shilling, PD, Shimoda, K, Simhandl, C, Slaney, CM, Pisanu, C, Squassina, A, Le Clerc, S, Lombardi, L, Baune, BT, Amare, AT, Schubert, KO, Hou, L, Clark, SR, Papiol, S, Cearns, M, Heilbronner, U, Degenhardt, F, Tekola-Ayele, F, Hsu, YH, Shekhtman, T, Adli, M, Akula, N, Akiyama, K, Ardau, R, Arias, B, Aubry, JM, Backlund, L, Bhattacharjee, AK, Bellivier, F, Benabarre, A, Bengesser, S, Biernacka, JM, Birner, A, Brichant-Petitjean, C, Cervantes, P, Chen, HC, Chillotti, C, Cichon, S, Cruceanu, C, Czerski, PM, Dalkner, N, Dayer, A, Del Zompo, M, DePaulo, JR, Étain, B, Jamain, S, Falkai, P, Forstner, AJ, Frisen, L, Frye, MA, Fullerton, JM, Gard, S, Garnham, JS, Goes, FS, Grigoroiu-Serbanescu, M, Grof, P, Hashimoto, R, Hauser, J, Herms, S, Hoffmann, P, Jiménez, E, Kahn, JP, Kassem, L, Kuo, PH, Kato, T, Kelsoe, JR, Kittel-Schneider, S, Ferensztajn-Rochowiak, E, König, B, Kusumi, I, Laje, G, Landén, M, Lavebratt, C, Leckband, SG, Tortorella, A, Manchia, M, Martinsson, L, McCarthy, MJ, McElroy, SL, Colom, F, Millischer, V, Mitjans, M, Mondimore, FM, Monteleone, P, Nievergelt, CM, Nöthen, MM, Novák, T, O’Donovan, C, Ozaki, N, Ösby, U, Pfennig, A, Potash, JB, Reif, A, Reininghaus, E, Rouleau, GA, Rybakowski, JK, Schalling, M, Schofield, PR, Schweizer, BW, Severino, G, Shilling, PD, Shimoda, K, Simhandl, C, Slaney, CM, Pisanu, C, and Squassina, A
Abstract: Bipolar affective disorder (BD) is a severe psychiatric illness, for which lithium (Li) is the gold standard for acute and maintenance therapies. The therapeutic response to Li in BD is heterogeneous and reliable biomarkers allowing patients stratification are still needed. A GWAS performed by the International Consortium on Lithium Genetics (ConLiGen) has recently identified genetic markers associated with treatment responses to Li in the human leukocyte antigens (HLA) region. To better understand the molecular mechanisms underlying this association, we have genetically imputed the classical alleles of the HLA region in the European patients of the ConLiGen cohort. We found our best signal for amino-acid variants belonging to the HLA-DRB1*11:01 classical allele, associated with a better response to Li (p < 1 × 10−3; FDR < 0.09 in the recessive model). Alanine or Leucine at position 74 of the HLA-DRB1 heavy chain was associated with a good response while Arginine or Glutamic acid with a poor response. As these variants have been implicated in common inflammatory/autoimmune processes, our findings strongly suggest that HLA-mediated low inflammatory background may contribute to the efficient response to Li in BD patients, while an inflammatory status overriding Li anti-inflammatory properties would favor a weak response.
Published: 2021

6. Association of polygenic score for major depression with response to lithium in patients with bipolar disorder

Author: Amare, AT, Schubert, KO, Hou, L, Clark, SR, Papiol, S, Cearns, M, Heilbronner, U, Degenhardt, F, Tekola-Ayele, F, Hsu, Y-H, Shekhtman, T, AdIi, M, Akula, N, Akiyama, K, Ardau, R, Arias, B, Aubry, J-M, Backlund, L, Bhattacharjee, K, Bellivier, F, Benabarre, A, Bengesser, S, Biernacka, JM, Birner, A, Brichant-Petitjean, C, Cervantes, P, Chen, H-C, Chillotti, C, Cichon, S, Cruceanu, C, Czerski, PM, Dalkner, N, Dayer, A, Del Zompo, M, DePaulo, JR, Etain, B, Jamain, S, Falkai, P, Forstner, AJ, Frisen, L, Frye, MA, Fullerton, JM, Gard, S, Garnham, JS, Goes, FS, Grigoroiu-Serbanescu, M, Grof, P, Hashimoto, R, Hauser, J, Herms, S, Hoffmann, P, Hofmann, A, Jimenez, E, Kahn, J-P, Kassem, L, Kuo, P-H, Kato, T, Kelsoe, JR, Kittel-Schneider, S, Kliwicki, S, Koenig, B, Kusumi, I, Laje, G, Landen, M, Lavebratt, C, Leboyer, M, Leckband, SG, Tortorella, A, Manchia, M, Martinsson, L, McCarthy, MJ, McElroy, SL, Colom, F, Mitjans, M, Mondimore, FM, Monteleone, P, Nievergelt, CM, Noethen, MM, Novak, T, O'Donovan, C, Ozaki, N, Osby, U, Pfennig, A, Potash, JB, Reif, A, Reininghaus, E, Rouleau, GA, Rybakowski, JK, Schalling, M, Schofield, PR, Schweizer, BW, Severino, G, Shilling, PD, Shimoda, K, Simhandl, C, Slaney, CM, Squassina, A, Stamm, T, Stopkova, P, Maj, M, Turecki, G, Vieta, E, Veeh, J, Witt, SH, Wright, A, Zandi, PP, Mitchell, PB, Bauer, M, Alda, M, Rietschel, M, McMahon, FJ, Schulze, TG, Baune, BT, Amare, AT, Schubert, KO, Hou, L, Clark, SR, Papiol, S, Cearns, M, Heilbronner, U, Degenhardt, F, Tekola-Ayele, F, Hsu, Y-H, Shekhtman, T, AdIi, M, Akula, N, Akiyama, K, Ardau, R, Arias, B, Aubry, J-M, Backlund, L, Bhattacharjee, K, Bellivier, F, Benabarre, A, Bengesser, S, Biernacka, JM, Birner, A, Brichant-Petitjean, C, Cervantes, P, Chen, H-C, Chillotti, C, Cichon, S, Cruceanu, C, Czerski, PM, Dalkner, N, Dayer, A, Del Zompo, M, DePaulo, JR, Etain, B, Jamain, S, Falkai, P, Forstner, AJ, Frisen, L, Frye, MA, Fullerton, JM, Gard, S, Garnham, JS, Goes, FS, Grigoroiu-Serbanescu, M, Grof, P, Hashimoto, R, Hauser, J, Herms, S, Hoffmann, P, Hofmann, A, Jimenez, E, Kahn, J-P, Kassem, L, Kuo, P-H, Kato, T, Kelsoe, JR, Kittel-Schneider, S, Kliwicki, S, Koenig, B, Kusumi, I, Laje, G, Landen, M, Lavebratt, C, Leboyer, M, Leckband, SG, Tortorella, A, Manchia, M, Martinsson, L, McCarthy, MJ, McElroy, SL, Colom, F, Mitjans, M, Mondimore, FM, Monteleone, P, Nievergelt, CM, Noethen, MM, Novak, T, O'Donovan, C, Ozaki, N, Osby, U, Pfennig, A, Potash, JB, Reif, A, Reininghaus, E, Rouleau, GA, Rybakowski, JK, Schalling, M, Schofield, PR, Schweizer, BW, Severino, G, Shilling, PD, Shimoda, K, Simhandl, C, Slaney, CM, Squassina, A, Stamm, T, Stopkova, P, Maj, M, Turecki, G, Vieta, E, Veeh, J, Witt, SH, Wright, A, Zandi, PP, Mitchell, PB, Bauer, M, Alda, M, Rietschel, M, McMahon, FJ, Schulze, TG, and Baune, BT
Abstract: Lithium is a first-line medication for bipolar disorder (BD), but only one in three patients respond optimally to the drug. Since evidence shows a strong clinical and genetic overlap between depression and bipolar disorder, we investigated whether a polygenic susceptibility to major depression is associated with response to lithium treatment in patients with BD. Weighted polygenic scores (PGSs) were computed for major depression (MD) at different GWAS p value thresholds using genetic data obtained from 2586 bipolar patients who received lithium treatment and took part in the Consortium on Lithium Genetics (ConLi+Gen) study. Summary statistics from genome-wide association studies in MD (135,458 cases and 344,901 controls) from the Psychiatric Genomics Consortium (PGC) were used for PGS weighting. Response to lithium treatment was defined by continuous scores and categorical outcome (responders versus non-responders) using measurements on the Alda scale. Associations between PGSs of MD and lithium treatment response were assessed using a linear and binary logistic regression modeling for the continuous and categorical outcomes, respectively. The analysis was performed for the entire cohort, and for European and Asian sub-samples. The PGSs for MD were significantly associated with lithium treatment response in multi-ethnic, European or Asian populations, at various p value thresholds. Bipolar patients with a low polygenic load for MD were more likely to respond well to lithium, compared to those patients with high polygenic load [lowest vs highest PGS quartiles, multi-ethnic sample: OR = 1.54 (95% CI: 1.18-2.01) and European sample: OR = 1.75 (95% CI: 1.30-2.36)]. While our analysis in the Asian sample found equivalent effect size in the same direction: OR = 1.71 (95% CI: 0.61-4.90), this was not statistically significant. Using PGS decile comparison, we found a similar trend of association between a high genetic loading for MD and lower response to lithium. Our findin
Published: 2021

7. Combining schizophrenia and depression polygenic risk scores improves the genetic prediction of lithium response in bipolar disorder patients

Author: Schubert, KO, Thalamuthu, A, Amare, AT, Frank, J, Streit, F, Adl, M, Akula, N, Akiyama, K, Ardau, R, Arias, B, Aubry, J-M, Backlund, L, Bhattacharjee, AK, Bellivier, F, Benabarre, A, Bengesser, S, Biernacka, JM, Birner, A, Marie-Claire, C, Cearns, M, Cervantes, P, Chen, H-C, Chillotti, C, Cichon, S, Clark, SR, Cruceanu, C, Czerski, PM, Dalkner, N, Dayer, A, Degenhardt, F, Del Zompo, M, DePaulo, JR, Etain, B, Falkai, P, Forstner, AJ, Frisen, L, Frye, MA, Fullerton, JM, Gard, S, Garnham, JS, Goes, FS, Grigoroiu-Serbanescu, M, Grof, P, Hashimoto, R, Hauser, J, Heilbronner, U, Herms, S, Hoffmann, P, Hou, L, Hsu, Y-H, Jamain, S, Jimenez, E, Kahn, J-P, Kassem, L, Kuo, P-H, Kato, T, Kelsoe, J, Kittel-Schneider, S, Ferensztajn-Rochowiak, E, Koenig, B, Kusumi, I, Laje, G, Landen, M, Lavebratt, C, Leboyer, M, Leckband, SG, Maj, M, Manchia, M, Martinsson, L, McCarthy, MJ, McElroy, S, Colom, F, Mitjans, M, Mondimore, FM, Monteleone, P, Nievergelt, CM, Noethen, MM, Novak, T, O'Donovan, C, Ozaki, N, Oesby, U, Papiol, S, Pfennig, A, Pisanu, C, Potash, JB, Reif, A, Reininghaus, E, Rouleau, GA, Rybakowski, JK, Schalling, M, Schofield, PR, Schweizer, BW, Severino, G, Shekhtman, T, Shilling, PD, Shimoda, K, Simhandl, C, Slaney, CM, Squassina, A, Stamm, T, Stopkova, P, Tekola-Ayele, F, Tortorella, A, Turecki, G, Veeh, J, Vieta, E, Witt, SH, Roberts, G, Zandi, PP, Alda, M, Bauer, M, McMahon, FJ, Mitchell, PB, Schulze, TG, Rietschel, M, Baune, BT, Schubert, KO, Thalamuthu, A, Amare, AT, Frank, J, Streit, F, Adl, M, Akula, N, Akiyama, K, Ardau, R, Arias, B, Aubry, J-M, Backlund, L, Bhattacharjee, AK, Bellivier, F, Benabarre, A, Bengesser, S, Biernacka, JM, Birner, A, Marie-Claire, C, Cearns, M, Cervantes, P, Chen, H-C, Chillotti, C, Cichon, S, Clark, SR, Cruceanu, C, Czerski, PM, Dalkner, N, Dayer, A, Degenhardt, F, Del Zompo, M, DePaulo, JR, Etain, B, Falkai, P, Forstner, AJ, Frisen, L, Frye, MA, Fullerton, JM, Gard, S, Garnham, JS, Goes, FS, Grigoroiu-Serbanescu, M, Grof, P, Hashimoto, R, Hauser, J, Heilbronner, U, Herms, S, Hoffmann, P, Hou, L, Hsu, Y-H, Jamain, S, Jimenez, E, Kahn, J-P, Kassem, L, Kuo, P-H, Kato, T, Kelsoe, J, Kittel-Schneider, S, Ferensztajn-Rochowiak, E, Koenig, B, Kusumi, I, Laje, G, Landen, M, Lavebratt, C, Leboyer, M, Leckband, SG, Maj, M, Manchia, M, Martinsson, L, McCarthy, MJ, McElroy, S, Colom, F, Mitjans, M, Mondimore, FM, Monteleone, P, Nievergelt, CM, Noethen, MM, Novak, T, O'Donovan, C, Ozaki, N, Oesby, U, Papiol, S, Pfennig, A, Pisanu, C, Potash, JB, Reif, A, Reininghaus, E, Rouleau, GA, Rybakowski, JK, Schalling, M, Schofield, PR, Schweizer, BW, Severino, G, Shekhtman, T, Shilling, PD, Shimoda, K, Simhandl, C, Slaney, CM, Squassina, A, Stamm, T, Stopkova, P, Tekola-Ayele, F, Tortorella, A, Turecki, G, Veeh, J, Vieta, E, Witt, SH, Roberts, G, Zandi, PP, Alda, M, Bauer, M, McMahon, FJ, Mitchell, PB, Schulze, TG, Rietschel, M, and Baune, BT
Abstract: Lithium is the gold standard therapy for Bipolar Disorder (BD) but its effectiveness differs widely between individuals. The molecular mechanisms underlying treatment response heterogeneity are not well understood, and personalized treatment in BD remains elusive. Genetic analyses of the lithium treatment response phenotype may generate novel molecular insights into lithium's therapeutic mechanisms and lead to testable hypotheses to improve BD management and outcomes. We used fixed effect meta-analysis techniques to develop meta-analytic polygenic risk scores (MET-PRS) from combinations of highly correlated psychiatric traits, namely schizophrenia (SCZ), major depression (MD) and bipolar disorder (BD). We compared the effects of cross-disorder MET-PRS and single genetic trait PRS on lithium response. For the PRS analyses, we included clinical data on lithium treatment response and genetic information for n = 2283 BD cases from the International Consortium on Lithium Genetics (ConLi+Gen; www.ConLiGen.org ). Higher SCZ and MD PRSs were associated with poorer lithium treatment response whereas BD-PRS had no association with treatment outcome. The combined MET2-PRS comprising of SCZ and MD variants (MET2-PRS) and a model using SCZ and MD-PRS sequentially improved response prediction, compared to single-disorder PRS or to a combined score using all three traits (MET3-PRS). Patients in the highest decile for MET2-PRS loading had 2.5 times higher odds of being classified as poor responders than patients with the lowest decile MET2-PRS scores. An exploratory functional pathway analysis of top MET2-PRS variants was conducted. Findings may inform the development of future testing strategies for personalized lithium prescribing in BD.
Published: 2021

8. Classical Human Leukocyte Antigen Alleles and C4 Haplotypes Are Not Significantly Associated With Depression

Author: Glanville, KP, Coleman, JR, Hanscombe, KB, Euesden, J, Choi, SW, Purves, KL, Breen, G, Air, TM, Andlauer, TFM, Baune, BT, Binder, EB, Blackwood, DHR, Boomsma, D, Buttenschon, HN, Colodro-Conde, L, Dannlowski, U, Direk, N, Dunn, EC, Forstner, AJ, de Geus, EJC, Grabe, HJ, Hamilton, SP, Jones, I, Jones, LA, Knowles, JA, Kutalik, Z, Levinson, DF, Lewis, G, Lind, PA, Lucae, S, Magnusson, PK, McGuffin, P, McIntosh, AM, Milaneschi, Y, Mors, O, Mostafavi, S, Mueller-Myhsok, B, Pedersen, NL, Penninx, BWJH, Potash, JB, Preisig, M, Ripke, S, Shi, J, Shyn, S, Smoller, JW, Streit, F, Sullivan, PF, Tiemeier, H, Uher, R, Van der Auwera, S, Weissman, MM, O'Reilly, PF, Lewis, CM, Wray, NR, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Adams, MJ, Agerbo, E, Bacanu, S-A, Baekvad-Hansen, M, Beekman, ATF, Bigdeli, TB, Bryois, J, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Clarke, T-K, Couvy-Duchesne, B, Craddock, N, Crawford, GE, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, Dolan, C, Eley, TC, Escott-Price, V, Kiadeh, FFH, Finucane, HK, Foo, JC, Frank, J, Gaspar, HA, Gill, M, Goes, FS, Gordon, SD, Grove, J, Hall, LS, Hansen, CS, Hansen, TF, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Horn, C, Hottenga, J-J, Hougaard, DM, Howard, DM, Ising, M, Jansen, R, Jorgenson, E, Kohane, IS, Kraft, J, Kretzschmar, WW, Li, Y, MacIntyre, DJ, MacKinnon, DF, Maier, RM, Maier, W, Marchini, J, Mbarek, H, McGrath, P, Medland, SE, Mehta, D, Middeldorp, CM, Mihailov, E, Milani, L, Mondimore, FM, Montgomery, GW, Mullins, N, Nauck, M, Ng, B, Nivard, MG, Nyholt, DR, Oskarsson, H, Owen, MJ, Painter, JN, Pedersen, CB, Pedersen, MG, Peterson, RE, Pettersson, E, Peyrot, WJ, Pistis, G, Posthuma, D, Quiroz, JA, Qvist, P, Rice, JP, Riley, BP, Rivera, M, Mirza, SS, Schoevers, R, Schulte, EC, Shen, L, Sigurdsson, E, Sinnamon, GCB, Smit, JH, Smith, DJ, Stefansson, H, Steinberg, S, Strohmaier, J, Tansey, KE, Teismann, H, Teumer, A, Thompson, W, Thomson, PA, Thorgeirsson, TE, Traylor, M, Treutlein, J, Trubetskoy, V, Uitterlinden, AG, Umbricht, D, van Hemert, AM, Viktorin, A, Visscher, PM, Wang, Y, Webb, BT, Weinsheimer, SM, Wellmann, J, Willemsen, G, Witt, SH, Wu, Y, Xi, HS, Yang, J, Zhang, F, Arolt, V, Berger, K, Cichon, S, DePaulo, JR, Domenici, E, Domschke, K, Esko, T, Hayward, C, Heath, AC, Kendler, KS, Kloiber, S, Li, QS, Madden, PAF, Martin, NG, Metspalu, A, Mortensen, PB, Nordentoft, M, Noethen, MM, O'Donovan, MC, Paciga, SA, Perlis, RH, Porteous, DJ, Rietschel, M, Schaefer, C, Schulze, TG, Stefansson, K, Voelzke, H, Werge, T, Borglum, AD, Glanville, KP, Coleman, JR, Hanscombe, KB, Euesden, J, Choi, SW, Purves, KL, Breen, G, Air, TM, Andlauer, TFM, Baune, BT, Binder, EB, Blackwood, DHR, Boomsma, D, Buttenschon, HN, Colodro-Conde, L, Dannlowski, U, Direk, N, Dunn, EC, Forstner, AJ, de Geus, EJC, Grabe, HJ, Hamilton, SP, Jones, I, Jones, LA, Knowles, JA, Kutalik, Z, Levinson, DF, Lewis, G, Lind, PA, Lucae, S, Magnusson, PK, McGuffin, P, McIntosh, AM, Milaneschi, Y, Mors, O, Mostafavi, S, Mueller-Myhsok, B, Pedersen, NL, Penninx, BWJH, Potash, JB, Preisig, M, Ripke, S, Shi, J, Shyn, S, Smoller, JW, Streit, F, Sullivan, PF, Tiemeier, H, Uher, R, Van der Auwera, S, Weissman, MM, O'Reilly, PF, Lewis, CM, Wray, NR, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Adams, MJ, Agerbo, E, Bacanu, S-A, Baekvad-Hansen, M, Beekman, ATF, Bigdeli, TB, Bryois, J, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Clarke, T-K, Couvy-Duchesne, B, Craddock, N, Crawford, GE, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, Dolan, C, Eley, TC, Escott-Price, V, Kiadeh, FFH, Finucane, HK, Foo, JC, Frank, J, Gaspar, HA, Gill, M, Goes, FS, Gordon, SD, Grove, J, Hall, LS, Hansen, CS, Hansen, TF, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Horn, C, Hottenga, J-J, Hougaard, DM, Howard, DM, Ising, M, Jansen, R, Jorgenson, E, Kohane, IS, Kraft, J, Kretzschmar, WW, Li, Y, MacIntyre, DJ, MacKinnon, DF, Maier, RM, Maier, W, Marchini, J, Mbarek, H, McGrath, P, Medland, SE, Mehta, D, Middeldorp, CM, Mihailov, E, Milani, L, Mondimore, FM, Montgomery, GW, Mullins, N, Nauck, M, Ng, B, Nivard, MG, Nyholt, DR, Oskarsson, H, Owen, MJ, Painter, JN, Pedersen, CB, Pedersen, MG, Peterson, RE, Pettersson, E, Peyrot, WJ, Pistis, G, Posthuma, D, Quiroz, JA, Qvist, P, Rice, JP, Riley, BP, Rivera, M, Mirza, SS, Schoevers, R, Schulte, EC, Shen, L, Sigurdsson, E, Sinnamon, GCB, Smit, JH, Smith, DJ, Stefansson, H, Steinberg, S, Strohmaier, J, Tansey, KE, Teismann, H, Teumer, A, Thompson, W, Thomson, PA, Thorgeirsson, TE, Traylor, M, Treutlein, J, Trubetskoy, V, Uitterlinden, AG, Umbricht, D, van Hemert, AM, Viktorin, A, Visscher, PM, Wang, Y, Webb, BT, Weinsheimer, SM, Wellmann, J, Willemsen, G, Witt, SH, Wu, Y, Xi, HS, Yang, J, Zhang, F, Arolt, V, Berger, K, Cichon, S, DePaulo, JR, Domenici, E, Domschke, K, Esko, T, Hayward, C, Heath, AC, Kendler, KS, Kloiber, S, Li, QS, Madden, PAF, Martin, NG, Metspalu, A, Mortensen, PB, Nordentoft, M, Noethen, MM, O'Donovan, MC, Paciga, SA, Perlis, RH, Porteous, DJ, Rietschel, M, Schaefer, C, Schulze, TG, Stefansson, K, Voelzke, H, Werge, T, and Borglum, AD
Abstract: BACKGROUND: The prevalence of depression is higher in individuals with autoimmune diseases, but the mechanisms underlying the observed comorbidities are unknown. Shared genetic etiology is a plausible explanation for the overlap, and in this study we tested whether genetic variation in the major histocompatibility complex (MHC), which is associated with risk for autoimmune diseases, is also associated with risk for depression. METHODS: We fine-mapped the classical MHC (chr6: 29.6-33.1 Mb), imputing 216 human leukocyte antigen (HLA) alleles and 4 complement component 4 (C4) haplotypes in studies from the Psychiatric Genomics Consortium Major Depressive Disorder Working Group and the UK Biobank. The total sample size was 45,149 depression cases and 86,698 controls. We tested for association between depression status and imputed MHC variants, applying both a region-wide significance threshold (3.9 × 10-6) and a candidate threshold (1.6 × 10-4). RESULTS: No HLA alleles or C4 haplotypes were associated with depression at the region-wide threshold. HLA-B*08:01 was associated with modest protection for depression at the candidate threshold for testing in HLA genes in the meta-analysis (odds ratio = 0.98, 95% confidence interval = 0.97-0.99). CONCLUSIONS: We found no evidence that an increased risk for depression was conferred by HLA alleles, which play a major role in the genetic susceptibility to autoimmune diseases, or C4 haplotypes, which are strongly associated with schizophrenia. These results suggest that any HLA or C4 variants associated with depression either are rare or have very modest effect sizes.
Published: 2020

9. Genome-wide gene-environment analyses of major depressive disorder and reported lifetime traumatic experiences in UK Biobank

Author: Coleman, JRI, Peyrot, WJ, Purves, KL, Davis, KAS, Rayner, C, Choi, SW, Hubel, C, Gaspar, HA, Kan, C, Van der Auwera, S, Adams, MJ, Lyall, DM, Choi, KW, Dunn, EC, Vassos, E, Danese, A, Maughan, B, Grabe, HJ, Lewis, CM, O'Reilly, PF, McIntosh, AM, Smith, DJ, Wray, NR, Hotopf, M, Eley, TC, Breen, G, Ripke, S, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Agerbo, E, Air, TM, Andlauer, TFM, Bacanu, S-A, Baekvad-Hansen, M, Beekman, ATF, Bigdeli, TB, Binder, EB, Bryois, J, Buttenschon, HN, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Clarke, T-K, Colodro-Conde, L, Couvy-Duchesne, B, Craddock, N, Crawford, GE, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, Direk, N, Dolan, CV, Escott-Price, V, Kiadeh, FFH, Finucane, HK, Foo, JC, Forstner, AJ, Frank, J, Gill, M, Goes, FS, Gordon, SD, Grove, J, Hall, LS, Hansen, CS, Hansen, TF, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Horn, C, Hottenga, J-J, Hougaard, DM, Howard, DM, Ising, M, Jansen, R, Jones, I, Jones, LA, Jorgenson, E, Knowles, JA, Kohane, IS, Kraft, J, Kretzschmar, WW, Kutalik, Z, Li, Y, Lind, PA, MacIntyre, DJ, MacKinnon, DF, Maier, RM, Maier, W, Marchini, J, Mbarek, H, McGrath, P, McGuffin, P, Medland, SE, Mehta, D, Middeldorp, CM, Mihailov, E, Milaneschi, Y, Milani, L, Mondimore, FM, Montgomery, GW, Mostafavi, S, Mullins, N, Nauck, M, Ng, B, Nivard, MG, Nyholt, DR, Oskarsson, H, Owen, MJ, Painter, JN, Pedersen, CB, Pedersen, MG, Peterson, RE, Pettersson, E, Pistis, G, Posthuma, D, Quiroz, JA, Qvist, P, Rice, JP, Riley, BP, Rivera, M, Mirza, SS, Schoevers, R, Schulte, EC, Shen, L, Shi, J, Shyn, SI, Sigurdsson, E, Sinnamon, GCB, Smit, JH, Stefansson, H, Steinberg, S, Streit, F, Strohmaier, J, Tansey, KE, Teismann, H, Teumer, A, Thompson, W, Thomson, PA, Thorgeirsson, TE, Traylor, M, Treutlein, J, Trubetskoy, V, Uitterlinden, AG, Umbricht, D, van Hemert, AM, Viktorin, A, Visscher, PM, Wang, Y, Webb, BT, Weinsheimer, SM, Wellmann, J, Willemsen, G, Witt, SH, Wu, Y, Xi, HS, Yang, J, Zhang, F, Arolt, V, Baune, BT, Berger, K, Boomsma, DI, Cichon, S, Dannlowski, U, de Geus, EJC, DePaulo, JR, Domenici, E, Domschke, K, Esko, T, Hamilton, SP, Hayward, C, Heath, AC, Kendler, KS, Kloiber, S, Lewis, G, Li, QS, Lucae, S, Madden, PAF, Magnusson, PK, Martin, NG, Metspalu, A, Mors, O, Mortensen, PB, Mueller-Myhsok, B, Nordentoft, M, Noethen, MM, O'Donovan, MC, Paciga, SA, Pedersen, NL, Penninx, BWJH, Perlis, RH, Porteous, DJ, Potash, JB, Preisig, M, Rietschel, M, Schaefer, C, Schulze, TG, Smoller, JW, Stefansson, K, Tiemeier, H, Uher, R, Volzke, H, Weissman, MM, Werge, T, Levinson, DF, Borglum, AD, Sullivan, PF, Coleman, JRI, Peyrot, WJ, Purves, KL, Davis, KAS, Rayner, C, Choi, SW, Hubel, C, Gaspar, HA, Kan, C, Van der Auwera, S, Adams, MJ, Lyall, DM, Choi, KW, Dunn, EC, Vassos, E, Danese, A, Maughan, B, Grabe, HJ, Lewis, CM, O'Reilly, PF, McIntosh, AM, Smith, DJ, Wray, NR, Hotopf, M, Eley, TC, Breen, G, Ripke, S, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Agerbo, E, Air, TM, Andlauer, TFM, Bacanu, S-A, Baekvad-Hansen, M, Beekman, ATF, Bigdeli, TB, Binder, EB, Bryois, J, Buttenschon, HN, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Clarke, T-K, Colodro-Conde, L, Couvy-Duchesne, B, Craddock, N, Crawford, GE, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, Direk, N, Dolan, CV, Escott-Price, V, Kiadeh, FFH, Finucane, HK, Foo, JC, Forstner, AJ, Frank, J, Gill, M, Goes, FS, Gordon, SD, Grove, J, Hall, LS, Hansen, CS, Hansen, TF, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Horn, C, Hottenga, J-J, Hougaard, DM, Howard, DM, Ising, M, Jansen, R, Jones, I, Jones, LA, Jorgenson, E, Knowles, JA, Kohane, IS, Kraft, J, Kretzschmar, WW, Kutalik, Z, Li, Y, Lind, PA, MacIntyre, DJ, MacKinnon, DF, Maier, RM, Maier, W, Marchini, J, Mbarek, H, McGrath, P, McGuffin, P, Medland, SE, Mehta, D, Middeldorp, CM, Mihailov, E, Milaneschi, Y, Milani, L, Mondimore, FM, Montgomery, GW, Mostafavi, S, Mullins, N, Nauck, M, Ng, B, Nivard, MG, Nyholt, DR, Oskarsson, H, Owen, MJ, Painter, JN, Pedersen, CB, Pedersen, MG, Peterson, RE, Pettersson, E, Pistis, G, Posthuma, D, Quiroz, JA, Qvist, P, Rice, JP, Riley, BP, Rivera, M, Mirza, SS, Schoevers, R, Schulte, EC, Shen, L, Shi, J, Shyn, SI, Sigurdsson, E, Sinnamon, GCB, Smit, JH, Stefansson, H, Steinberg, S, Streit, F, Strohmaier, J, Tansey, KE, Teismann, H, Teumer, A, Thompson, W, Thomson, PA, Thorgeirsson, TE, Traylor, M, Treutlein, J, Trubetskoy, V, Uitterlinden, AG, Umbricht, D, van Hemert, AM, Viktorin, A, Visscher, PM, Wang, Y, Webb, BT, Weinsheimer, SM, Wellmann, J, Willemsen, G, Witt, SH, Wu, Y, Xi, HS, Yang, J, Zhang, F, Arolt, V, Baune, BT, Berger, K, Boomsma, DI, Cichon, S, Dannlowski, U, de Geus, EJC, DePaulo, JR, Domenici, E, Domschke, K, Esko, T, Hamilton, SP, Hayward, C, Heath, AC, Kendler, KS, Kloiber, S, Lewis, G, Li, QS, Lucae, S, Madden, PAF, Magnusson, PK, Martin, NG, Metspalu, A, Mors, O, Mortensen, PB, Mueller-Myhsok, B, Nordentoft, M, Noethen, MM, O'Donovan, MC, Paciga, SA, Pedersen, NL, Penninx, BWJH, Perlis, RH, Porteous, DJ, Potash, JB, Preisig, M, Rietschel, M, Schaefer, C, Schulze, TG, Smoller, JW, Stefansson, K, Tiemeier, H, Uher, R, Volzke, H, Weissman, MM, Werge, T, Levinson, DF, Borglum, AD, and Sullivan, PF
Abstract: Depression is more frequent among individuals exposed to traumatic events. Both trauma exposure and depression are heritable. However, the relationship between these traits, including the role of genetic risk factors, is complex and poorly understood. When modelling trauma exposure as an environmental influence on depression, both gene-environment correlations and gene-environment interactions have been observed. The UK Biobank concurrently assessed Major Depressive Disorder (MDD) and self-reported lifetime exposure to traumatic events in 126,522 genotyped individuals of European ancestry. We contrasted genetic influences on MDD stratified by reported trauma exposure (final sample size range: 24,094-92,957). The SNP-based heritability of MDD with reported trauma exposure (24%) was greater than MDD without reported trauma exposure (12%). Simulations showed that this is not confounded by the strong, positive genetic correlation observed between MDD and reported trauma exposure. We also observed that the genetic correlation between MDD and waist circumference was only significant in individuals reporting trauma exposure (rg = 0.24, p = 1.8 × 10-7 versus rg = -0.05, p = 0.39 in individuals not reporting trauma exposure, difference p = 2.3 × 10-4). Our results suggest that the genetic contribution to MDD is greater when reported trauma is present, and that a complex relationship exists between reported trauma exposure, body composition, and MDD.
Published: 2020

10. Revealing the complex genetic architecture of obsessive-compulsive disorder using meta-analysis

Author: nternational Obsessive Compulsive Disorder Foundation Genetics Collaborative (IOCDF-GC), OCD Collaborative Genetics Association Studies (OCGAS): Arnold PD, Askland KD, Barlassina C, Bellodi L, Bienvenu OJ, Black D, Bloch M, Brentani H, Burton CL, Camarena B, Cappi C, Cath D, Cavallini M, Conti D, Cook E, Coric V, Cullen BA, Cusi D, Davis LK, Delorme R, Denys D, Derks E, Eapen V, Edlund C, Erdman L, Falkai P, Figee M, Fyer AJ, Geller DA, Goes FS, Grabe H, Grados MA, Greenberg BD, Grünblatt E, Guo W, Hanna GL, Hemmings S, Hounie AG, Jenicke M, Keenan C, Kennedy J, Khramtsova EA, Konkashbaev A, Knowles JA, Krasnow J, Lange C, Lanzagorta N, Leboyer M, Lennertz L, Li B, Liang KY, Lochner C, Macciardi F, Maher B, Maier W, Marconi M, Mathews CA, Matthesien M, McCracken JT, McLaughlin NC, Miguel EC, Moessner R, Murphy DL, Neale B, Nestadt G, Nestadt P, Nicolini H, Nurmi E, Osiecki L, Pauls DL, Piacentini J, Posthuma D, Pulver AE, Qin HD, Rasmussen SA, Rauch S, Richter MA, Riddle MA, Ripke S, Ruhrmann S, Sampaio AS, Samuels JF, Scharf JM, Shugart YY, Smit J, Stein D, Stewart SE, Turiel M, Vallada H, Veenstra-VanderWeele J, Wagner M, Walitza S, Wang Y, Wendland J, Vulink N, Yu D, Zai G., Amsterdam Neuroscience - Complex Trait Genetics, Complex Trait Genetics, Psychiatry, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Amsterdam Reproduction & Development (AR&D), Human genetics, ANS - Compulsivity, Impulsivity & Attention, Adult Psychiatry, APH - Mental Health, Arnold, Paul D, Askland, Kathleen D, Barlassina, Cristina, Bellodi, Laura, Bienvenu, O. J, Black, Donald, Bloch, Michael, Brentani, Helena, Burton, Christie L, Camarena, Beatriz, Cappi, Carolina, Cath, Danielle, Cavallini, Maria, Conti, David, Cook, Edwin, Coric, Vladimir, Cullen, Bernadette A, Cusi, Danielle, Davis, Lea K, Delorme, Richard, Denys, Damiaan, Derks, Eske, Eapen, Valsamma, Edlund, Christopher, Erdman, Lauren, Falkai, Peter, Figee, Martijn, Fyer, Abigail J, Geller, Daniel A, Goes, Fernando S, Grabe, Han, Grados, Marcos A, Greenberg, Benjamin D, Grünblatt, Edna, Guo, Wei, Hanna, Gregory L, Hemmings, Sian, Hounie, Ana G, Jenicke, Michael, Keenan, Clare, Kennedy, Jame, Khramtsova, Ekaterina A, Konkashbaev, Anuar, Knowles, James A, Krasnow, Janice, Lange, Cristophe, Lanzagorta, Nuria, Leboyer, Marion, Lennertz, Leonhard, Li, Bingbin, Liang, K. y, Lochner, Christine, Macciardi, Fabio, Maher, Brion, Maier, Wolfgang, Marconi, Maurizio, Mathews, Carol A, Matthesien, Manuel, Mccracken, James T, Mclaughlin, Nicole C, Miguel, Euripedes C, Moessner, Rainald, Murphy, Dennis L, Neale, Benjamin, Nestadt, Gerald, Nestadt, Paul, Nicolini, Humberto, Nurmi, Ericka, Osiecki, Lisa, Pauls, David L, Piacentini, John, Posthuma, Danielle, Pulver, Ann E, Qin, H. d, Rasmussen, Steven A, Rauch, Scott, Richter, Margaret A, Riddle, Mark A, Ripke, Stephan, Ruhrmann, Stephan, Sampaio, Aline S, Samuels, Jack F, Scharf, Jeremiah M, Shugart, Yin Yao, Smit, Jan, Stein, Daniel, Stewart, S. Evelyn, Turiel, Maurizio, Vallada, Homero, Veenstra vanderweele, Jeremy, Wagner, Michael, Walitza, Susanne, Wang, Y, Wendland, Jen, Vulink, Nienke, Yu, Dongmei, Zai, Gwyneth, and Netherlands Institute for Neuroscience (NIN)
Subjects: 0301 basic medicine, Genetics, TRANSTORNO OBSESSIVO-COMPULSIVO, Single-nucleotide polymorphism, Odds ratio, Biology, Heritability, Confidence interval, Genetic architecture, Minor allele frequency, 03 medical and health sciences, Cellular and Molecular Neuroscience, Psychiatry and Mental health, 030104 developmental biology, 0302 clinical medicine, Journal Article, SNP, SDG 2 - Zero Hunger, Molecular Biology, 030217 neurology & neurosurgery, Genetic association
Abstract: Two obsessive-compulsive disorder (OCD) genome-wide association studies (GWASs) have been published by independent OCD consortia, the International Obsessive-Compulsive Disorder Foundation Genetics Collaborative (IOCDF-GC) and the OCD Collaborative Genetics Association Study (OCGAS), but many of the top-ranked signals were supported in only one study. We therefore conducted a meta-analysis from the two consortia, investigating a total of 2688 individuals of European ancestry with OCD and 7037 genomically matched controls. No single-nucleotide polymorphisms (SNPs) reached genome-wide significance. However, in comparison with the two individual GWASs, the distribution of P-values shifted toward significance. The top haplotypic blocks were tagged with rs4733767 (P=7.1 × 10(-7); odds ratio (OR)=1.21; confidence interval (CI): 1.12-1.31, CASC8/CASC11), rs1030757 (P=1.1 × 10(-6); OR=1.18; CI: 1.10-1.26, GRID2) and rs12504244 (P=1.6 × 10(-6); OR=1.18; CI: 1.11-1.27, KIT). Variants located in or near the genes ASB13, RSPO4, DLGAP1, PTPRD, GRIK2, FAIM2 and CDH20, identified in linkage peaks and the original GWASs, were among the top signals. Polygenic risk scores for each individual study predicted case-control status in the other by explaining 0.9% (P=0.003) and 0.3% (P=0.0009) of the phenotypic variance in OCGAS and the European IOCDF-GC target samples, respectively. The common SNP heritability in the combined OCGAS and IOCDF-GC sample was estimated to be 0.28 (s.e.=0.04). Strikingly, ∼65% of the SNP-based heritability in the OCGAS sample was accounted for by SNPs with minor allele frequencies of ⩾40%. This joint analysis constituting the largest single OCD genome-wide study to date represents a major integrative step in elucidating the genetic causes of OCD.Molecular Psychiatry advance online publication, 1 August 2017; doi:10.1038/mp.2017.154.
Published: 2018

11. Investigating polygenic burden in age at disease onset in bipolar disorder: Findings from an international multicentric study

Author: Kalman, JL, Papiol, S, Forstner, AJ, Heilbronner, U, Degenhardt, F, Strohmaier, J, Adli, M, Adorjan, K, Akula, N, Alda, M, Anderson-Schmidt, H, Andlauer, TFM, Anghelescu, IG, Ardau, R, Arias, B, Arolt, V, Aubry, JM, Backlund, L, Bartholdi, K, Bauer, M, Baune, BT, Becker, T, Bellivier, F, Benabarre, A, Bengesser, S, Bhattacharjee, AK, Biernacka, JM, Birner, A, Brichant-Petitjean, C, Budde, M, Cervantes, P, Chillotti, C, Cichon, S, Clark, SR, Colom, F, Comes, AL, Cruceanu, C, Czerski, PM, Dannlowski, U, Dayer, A, Del Zompo, M, DePaulo, JR, Dietrich, DE, Étain, B, Ethofer, T, Falkai, P, Fallgatter, A, Figge, C, Flatau, L, Folkerts, H, Frisen, L, Frye, MA, Fullerton, JM, Gade, K, Gard, S, Garnham, JS, Goes, FS, Grigoroiu-Serbanescu, M, Gryaznova, A, Hake, M, Hauser, J, Herms, S, Hoffmann, P, Hou, L, Jäger, M, Jamain, S, Jiménez, E, Juckel, G, Kahn, JP, Kassem, L, Kelsoe, J, Kittel-Schneider, S, Kliwicki, S, Klohn-Sagatholislam, F, Koller, M, König, B, Konrad, C, Lackner, N, Laje, G, Landén, M, Lang, FU, Lavebratt, C, Leboyer, M, Leckband, SG, Maj, M, Manchia, M, Martinsson, L, McCarthy, MJ, McElroy, SL, McMahon, FJ, Mitchell, PB, Mitjans, M, Mondimore, FM, Monteleone, P, Nieratschker, V, Nievergelt, CM, Novák, T, Ösby, U, Pfennig, A, Potash, JB, Kalman, JL, Papiol, S, Forstner, AJ, Heilbronner, U, Degenhardt, F, Strohmaier, J, Adli, M, Adorjan, K, Akula, N, Alda, M, Anderson-Schmidt, H, Andlauer, TFM, Anghelescu, IG, Ardau, R, Arias, B, Arolt, V, Aubry, JM, Backlund, L, Bartholdi, K, Bauer, M, Baune, BT, Becker, T, Bellivier, F, Benabarre, A, Bengesser, S, Bhattacharjee, AK, Biernacka, JM, Birner, A, Brichant-Petitjean, C, Budde, M, Cervantes, P, Chillotti, C, Cichon, S, Clark, SR, Colom, F, Comes, AL, Cruceanu, C, Czerski, PM, Dannlowski, U, Dayer, A, Del Zompo, M, DePaulo, JR, Dietrich, DE, Étain, B, Ethofer, T, Falkai, P, Fallgatter, A, Figge, C, Flatau, L, Folkerts, H, Frisen, L, Frye, MA, Fullerton, JM, Gade, K, Gard, S, Garnham, JS, Goes, FS, Grigoroiu-Serbanescu, M, Gryaznova, A, Hake, M, Hauser, J, Herms, S, Hoffmann, P, Hou, L, Jäger, M, Jamain, S, Jiménez, E, Juckel, G, Kahn, JP, Kassem, L, Kelsoe, J, Kittel-Schneider, S, Kliwicki, S, Klohn-Sagatholislam, F, Koller, M, König, B, Konrad, C, Lackner, N, Laje, G, Landén, M, Lang, FU, Lavebratt, C, Leboyer, M, Leckband, SG, Maj, M, Manchia, M, Martinsson, L, McCarthy, MJ, McElroy, SL, McMahon, FJ, Mitchell, PB, Mitjans, M, Mondimore, FM, Monteleone, P, Nieratschker, V, Nievergelt, CM, Novák, T, Ösby, U, Pfennig, A, and Potash, JB
Abstract: Objectives: Bipolar disorder (BD) with early disease onset is associated with an unfavorable clinical outcome and constitutes a clinically and biologically homogenous subgroup within the heterogeneous BD spectrum. Previous studies have found an accumulation of early age at onset (AAO) in BD families and have therefore hypothesized that there is a larger genetic contribution to the early-onset cases than to late onset BD. To investigate the genetic background of this subphenotype, we evaluated whether an increased polygenic burden of BD- and schizophrenia (SCZ)-associated risk variants is associated with an earlier AAO in BD patients. Methods: A total of 1995 BD type 1 patients from the Consortium of Lithium Genetics (ConLiGen), PsyCourse and Bonn-Mannheim samples were genotyped and their BD and SCZ polygenic risk scores (PRSs) were calculated using the summary statistics of the Psychiatric Genomics Consortium as a training data set. AAO was either separated into onset groups of clinical interest (childhood and adolescence [≤18 years] vs adulthood [>18 years]) or considered as a continuous measure. The associations between BD- and SCZ-PRSs and AAO were evaluated with regression models. Results: BD- and SCZ-PRSs were not significantly associated with age at disease onset. Results remained the same when analyses were stratified by site of recruitment. Conclusions: The current study is the largest conducted so far to investigate the association between the cumulative BD and SCZ polygenic risk and AAO in BD patients. The reported negative results suggest that such a polygenic influence, if there is any, is not large, and highlight the importance of conducting further, larger scale studies to obtain more information on the genetic architecture of this clinically relevant phenotype.
Published: 2019

12. Evidence for increased genetic risk load for major depression in patients assigned to electroconvulsive therapy

Author: Foo, JC, Streit, F, Frank, J, Witt, SH, Treutlein, J, Baune, BT, Moebus, S, Joeckel, K-H, Forstner, AJ, Noethen, MM, Rietschel, M, Sartorius, A, Kranaster, L, Wray, NR, Ripke, S, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Adams, MJ, Agerbo, E, Air, TM, Andlauer, TFM, Bacanu, S-A, Baekvad-Hansen, M, Beekman, ATF, Bigdeli, TB, Binder, EB, Blackwood, DHR, Bryois, J, Buttenschon, HN, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Clarke, T-K, Coleman, JRI, Colodro-Conde, L, Couvy-Duchesne, B, Craddock, N, Crawford, GE, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, Direk, N, Dolan, CV, Dunn, EC, Eley, TC, Escott-Price, V, Kiadeh, FFH, Finucane, HK, Gaspar, HA, Gill, M, Goes, FS, Gordon, SD, Grove, J, Hall, LS, Hansen, CS, Hansen, TF, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Horn, C, Hottenga, J-J, Hougaard, DM, Ising, M, Jansen, R, Jones, I, Jones, LA, Jorgenson, E, Knowles, JA, Kohane, IS, Kraft, J, Kretzschmar, WW, Krogh, J, Kutalik, Z, Li, Y, Lind, PA, MacIntyre, DJ, MacKinnon, DF, Maier, RM, Maier, W, Marchini, J, Mbarek, H, McGrath, P, McGuffin, P, Medland, SE, Mehta, D, Middeldorp, CM, Mihailov, E, Milaneschi, Y, Milani, L, Mondimore, FM, Montgomery, GW, Mostafavi, S, Mullins, N, Nauck, M, Ng, B, Nivard, MG, Nyholt, DR, O'Reilly, PF, Oskarsson, H, Owen, MJ, Painter, JN, Pedersen, CB, Pedersen, MG, Peterson, RE, Pettersson, E, Peyrot, WJ, Pistis, G, Posthuma, D, Quiroz, JA, Qvist, P, Rice, JP, Riley, BP, Rivera, M, Mirza, SS, Schoevers, R, Schulte, EC, Shen, L, Shi, J, Shyn, SI, Sigurdsson, E, Sinnamon, GCB, Smit, JH, Smith, DJ, Stefansson, H, Steinberg, S, Strohmaier, J, Tansey, KE, Teismann, H, Teumer, A, Thompson, W, Thomson, PA, Thorgeirsson, TE, Traylor, M, Trubetskoy, V, Uitterlinden, AG, Umbricht, D, Van der Auwera, S, van Hemert, AM, Viktorin, A, Visscher, PM, Wang, Y, Webb, BT, Weinsheimer, SM, Wellmann, J, Willemsen, G, Wu, Y, Xi, HS, Yang, J, Zhang, F, Arolt, V, Berger, K, Boomsma, DI, Cichon, S, Dannlowski, U, de Geus, EJC, DePaulo, JR, Domenici, E, Domschke, K, Esko, T, Grabe, HJ, Hamilton, SP, Hayward, C, Heath, AC, Kendler, KS, Kloiber, S, Lewis, G, Li, QS, Lucae, S, Madden, PAF, Magnusson, PK, Martin, NG, McIntosh, AM, Metspalu, A, Mors, O, Mortensen, PB, Mueller-Myhsok, B, Nordentoft, M, O'Donovan, MC, Paciga, SA, Pedersen, NL, Penninx, BWJH, Perlis, RH, Porteous, DJ, Potash, JB, Preisig, M, Schaefer, C, Schulze, TG, Smoller, JW, Stefansson, K, Tiemeier, H, Uher, R, Voelzke, H, Weissman, MM, Werge, T, Lewis, CM, Levinson, DF, Breen, G, Borglum, AD, Sullivan, PF, Foo, JC, Streit, F, Frank, J, Witt, SH, Treutlein, J, Baune, BT, Moebus, S, Joeckel, K-H, Forstner, AJ, Noethen, MM, Rietschel, M, Sartorius, A, Kranaster, L, Wray, NR, Ripke, S, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Adams, MJ, Agerbo, E, Air, TM, Andlauer, TFM, Bacanu, S-A, Baekvad-Hansen, M, Beekman, ATF, Bigdeli, TB, Binder, EB, Blackwood, DHR, Bryois, J, Buttenschon, HN, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Clarke, T-K, Coleman, JRI, Colodro-Conde, L, Couvy-Duchesne, B, Craddock, N, Crawford, GE, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, Direk, N, Dolan, CV, Dunn, EC, Eley, TC, Escott-Price, V, Kiadeh, FFH, Finucane, HK, Gaspar, HA, Gill, M, Goes, FS, Gordon, SD, Grove, J, Hall, LS, Hansen, CS, Hansen, TF, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Horn, C, Hottenga, J-J, Hougaard, DM, Ising, M, Jansen, R, Jones, I, Jones, LA, Jorgenson, E, Knowles, JA, Kohane, IS, Kraft, J, Kretzschmar, WW, Krogh, J, Kutalik, Z, Li, Y, Lind, PA, MacIntyre, DJ, MacKinnon, DF, Maier, RM, Maier, W, Marchini, J, Mbarek, H, McGrath, P, McGuffin, P, Medland, SE, Mehta, D, Middeldorp, CM, Mihailov, E, Milaneschi, Y, Milani, L, Mondimore, FM, Montgomery, GW, Mostafavi, S, Mullins, N, Nauck, M, Ng, B, Nivard, MG, Nyholt, DR, O'Reilly, PF, Oskarsson, H, Owen, MJ, Painter, JN, Pedersen, CB, Pedersen, MG, Peterson, RE, Pettersson, E, Peyrot, WJ, Pistis, G, Posthuma, D, Quiroz, JA, Qvist, P, Rice, JP, Riley, BP, Rivera, M, Mirza, SS, Schoevers, R, Schulte, EC, Shen, L, Shi, J, Shyn, SI, Sigurdsson, E, Sinnamon, GCB, Smit, JH, Smith, DJ, Stefansson, H, Steinberg, S, Strohmaier, J, Tansey, KE, Teismann, H, Teumer, A, Thompson, W, Thomson, PA, Thorgeirsson, TE, Traylor, M, Trubetskoy, V, Uitterlinden, AG, Umbricht, D, Van der Auwera, S, van Hemert, AM, Viktorin, A, Visscher, PM, Wang, Y, Webb, BT, Weinsheimer, SM, Wellmann, J, Willemsen, G, Wu, Y, Xi, HS, Yang, J, Zhang, F, Arolt, V, Berger, K, Boomsma, DI, Cichon, S, Dannlowski, U, de Geus, EJC, DePaulo, JR, Domenici, E, Domschke, K, Esko, T, Grabe, HJ, Hamilton, SP, Hayward, C, Heath, AC, Kendler, KS, Kloiber, S, Lewis, G, Li, QS, Lucae, S, Madden, PAF, Magnusson, PK, Martin, NG, McIntosh, AM, Metspalu, A, Mors, O, Mortensen, PB, Mueller-Myhsok, B, Nordentoft, M, O'Donovan, MC, Paciga, SA, Pedersen, NL, Penninx, BWJH, Perlis, RH, Porteous, DJ, Potash, JB, Preisig, M, Schaefer, C, Schulze, TG, Smoller, JW, Stefansson, K, Tiemeier, H, Uher, R, Voelzke, H, Weissman, MM, Werge, T, Lewis, CM, Levinson, DF, Breen, G, Borglum, AD, and Sullivan, PF
Abstract: Electroconvulsive therapy (ECT) is the treatment of choice for severe and treatment-resistant depression; disorder severity and unfavorable treatment outcomes are shown to be influenced by an increased genetic burden for major depression (MD). Here, we tested whether ECT assignment and response/nonresponse are associated with an increased genetic burden for major depression (MD) using polygenic risk score (PRS), which summarize the contribution of disease-related common risk variants. Fifty-one psychiatric inpatients suffering from a major depressive episode underwent ECT. MD-PRS were calculated for these inpatients and a separate population-based sample (n = 3,547 healthy; n = 426 self-reported depression) based on summary statistics from the Psychiatric Genomics Consortium MDD-working group (Cases: n = 59,851; Controls: n = 113,154). MD-PRS explained a significant proportion of disease status between ECT patients and healthy controls (p = .022, R2 = 1.173%); patients showed higher MD-PRS. MD-PRS in population-based depression self-reporters were intermediate between ECT patients and controls (n.s.). Significant associations between MD-PRS and ECT response (50% reduction in Hamilton depression rating scale scores) were not observed. Our findings indicate that ECT cohorts show an increased genetic burden for MD and are consistent with the hypothesis that treatment-resistant MD patients represent a subgroup with an increased genetic risk for MD. Larger samples are needed to better substantiate these findings.
Published: 2019

13. Genome-wide by environment interaction studies of depressive symptoms and psychosocial stress in UK Biobank and Generation Scotland

Author: Arnau-Soler, A, Macdonald-Dunlop, E, Adams, MJ, Clarke, T-K, MacIntyre, DJ, Milburn, K, Navrady, L, Hayward, C, McIntosh, AM, Thomson, PA, Wray, NR, Ripke, S, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Agerbo, E, Air, TM, Andlauer, TFM, Bacanu, S-A, Baekvad-Hansen, M, Beekman, ATF, Bigdeli, TB, Binder, EB, Blackwood, DHR, Bryois, J, Buttenscon, HN, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Coleman, JR, Colodro-Conde, L, Couvy-Duchesne, B, Craddock, N, Rawford, GEC, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, Direk, N, Dolan, C, Dunn, EC, Eley, TC, Escott-Price, V, Kiadeh, FFH, Finucane, HK, Foo, JC, Forstner, AJ, Frank, J, Gaspar, HA, Gill, M, Goes, FS, Gordon, SD, Grove, J, Hall, LS, Hansen, CS, Hansen, TF, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Horn, C, Hottenga, J-J, Hougaard, DM, Ising, M, Jansen, R, Jones, I, Jones, LA, Jorgenson, E, Knowles, JA, Kohane, IS, Kraft, J, Kretzschmar, WW, Krogh, J, Kutalik, Z, Li, Y, Lind, PA, Macintyre, DJ, MacKinnon, DF, Maier, RM, Maier, W, Marchini, J, Mbarek, H, McGrath, P, McGuffin, P, Medland, SE, Mehta, D, Middeldorp, CM, Mihailov, E, Milaneschi, Y, Milani, L, Mondimore, FM, Montgomery, GW, Mostafavi, S, Mullins, N, Nauck, M, Ng, B, Nivard, MG, Nyholt, DR, O'Reilly, PF, Oskarsson, H, Owen, MJ, Painter, JN, Pedersen, CB, Pedersen, MG, Peterson, RE, Pettersson, E, Peyrot, WJ, Pistis, G, Posthuma, D, Quiroz, JA, Qvist, P, Rice, JP, Riley, BP, Rivera, M, Mirza, SS, Schoevers, R, Schulte, EC, Shen, L, Shi, J, Shyn, S, Sigurdsson, E, Sinnamon, GCB, Smit, JH, Smith, DJ, Stefansson, H, Steinberg, S, Streit, F, Strohmaier, J, Tansey, KE, Teismann, H, Teumer, A, Thompson, W, Thorgeirsson, TE, Traylor, M, Treutlein, J, Trubetskoy, V, Uitterlinden, AG, Umbricht, D, Van der Auwera, S, van Hemert, AM, Viktorin, A, Visscher, PM, Wang, Y, Webb, BT, Weinsheimer, SM, Wellmann, J, Willemsen, G, Witt, SH, Wu, Y, Xi, HS, Yang, J, Zhang, F, Arolt, V, Baune, BT, Berger, K, Boomsma, D, Cichon, S, Dannlowski, U, de Geus, EJC, DePaulo, JR, Domenici, E, Domschke, K, Esko, T, Grabe, HJ, Hamilton, SP, Heath, AC, Kendler, KS, Kloiber, S, Lewis, G, Li, QS, Lucae, S, Madden, PAF, Magnusson, PK, Martin, NG, Metspalu, A, Mors, O, Mortensen, PB, Mueller-Myhsok, B, Nordentoft, M, Noethen, MM, O'Donovan, MC, Paciga, SA, Pedersen, NL, Penninx, BWJH, Perlis, RH, Porteous, DJ, Potash, JB, Preisig, M, Rietschel, M, Schaefer, C, Schulze, TG, Smoller, JW, Stefansson, K, Tiemeier, H, Uher, R, Voelzke, H, Weissman, MM, Werge, T, Lewis, CM, Levinson, DF, Breen, G, Borglum, ASD, Sullivan, PF, Arnau-Soler, A, Macdonald-Dunlop, E, Adams, MJ, Clarke, T-K, MacIntyre, DJ, Milburn, K, Navrady, L, Hayward, C, McIntosh, AM, Thomson, PA, Wray, NR, Ripke, S, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Agerbo, E, Air, TM, Andlauer, TFM, Bacanu, S-A, Baekvad-Hansen, M, Beekman, ATF, Bigdeli, TB, Binder, EB, Blackwood, DHR, Bryois, J, Buttenscon, HN, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Coleman, JR, Colodro-Conde, L, Couvy-Duchesne, B, Craddock, N, Rawford, GEC, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, Direk, N, Dolan, C, Dunn, EC, Eley, TC, Escott-Price, V, Kiadeh, FFH, Finucane, HK, Foo, JC, Forstner, AJ, Frank, J, Gaspar, HA, Gill, M, Goes, FS, Gordon, SD, Grove, J, Hall, LS, Hansen, CS, Hansen, TF, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Horn, C, Hottenga, J-J, Hougaard, DM, Ising, M, Jansen, R, Jones, I, Jones, LA, Jorgenson, E, Knowles, JA, Kohane, IS, Kraft, J, Kretzschmar, WW, Krogh, J, Kutalik, Z, Li, Y, Lind, PA, Macintyre, DJ, MacKinnon, DF, Maier, RM, Maier, W, Marchini, J, Mbarek, H, McGrath, P, McGuffin, P, Medland, SE, Mehta, D, Middeldorp, CM, Mihailov, E, Milaneschi, Y, Milani, L, Mondimore, FM, Montgomery, GW, Mostafavi, S, Mullins, N, Nauck, M, Ng, B, Nivard, MG, Nyholt, DR, O'Reilly, PF, Oskarsson, H, Owen, MJ, Painter, JN, Pedersen, CB, Pedersen, MG, Peterson, RE, Pettersson, E, Peyrot, WJ, Pistis, G, Posthuma, D, Quiroz, JA, Qvist, P, Rice, JP, Riley, BP, Rivera, M, Mirza, SS, Schoevers, R, Schulte, EC, Shen, L, Shi, J, Shyn, S, Sigurdsson, E, Sinnamon, GCB, Smit, JH, Smith, DJ, Stefansson, H, Steinberg, S, Streit, F, Strohmaier, J, Tansey, KE, Teismann, H, Teumer, A, Thompson, W, Thorgeirsson, TE, Traylor, M, Treutlein, J, Trubetskoy, V, Uitterlinden, AG, Umbricht, D, Van der Auwera, S, van Hemert, AM, Viktorin, A, Visscher, PM, Wang, Y, Webb, BT, Weinsheimer, SM, Wellmann, J, Willemsen, G, Witt, SH, Wu, Y, Xi, HS, Yang, J, Zhang, F, Arolt, V, Baune, BT, Berger, K, Boomsma, D, Cichon, S, Dannlowski, U, de Geus, EJC, DePaulo, JR, Domenici, E, Domschke, K, Esko, T, Grabe, HJ, Hamilton, SP, Heath, AC, Kendler, KS, Kloiber, S, Lewis, G, Li, QS, Lucae, S, Madden, PAF, Magnusson, PK, Martin, NG, Metspalu, A, Mors, O, Mortensen, PB, Mueller-Myhsok, B, Nordentoft, M, Noethen, MM, O'Donovan, MC, Paciga, SA, Pedersen, NL, Penninx, BWJH, Perlis, RH, Porteous, DJ, Potash, JB, Preisig, M, Rietschel, M, Schaefer, C, Schulze, TG, Smoller, JW, Stefansson, K, Tiemeier, H, Uher, R, Voelzke, H, Weissman, MM, Werge, T, Lewis, CM, Levinson, DF, Breen, G, Borglum, ASD, and Sullivan, PF
Abstract: Stress is associated with poorer physical and mental health. To improve our understanding of this link, we performed genome-wide association studies (GWAS) of depressive symptoms and genome-wide by environment interaction studies (GWEIS) of depressive symptoms and stressful life events (SLE) in two UK population-based cohorts (Generation Scotland and UK Biobank). No SNP was individually significant in either GWAS, but gene-based tests identified six genes associated with depressive symptoms in UK Biobank (DCC, ACSS3, DRD2, STAG1, FOXP2 and KYNU; p < 2.77 × 10-6). Two SNPs with genome-wide significant GxE effects were identified by GWEIS in Generation Scotland: rs12789145 (53-kb downstream PIWIL4; p = 4.95 × 10-9; total SLE) and rs17070072 (intronic to ZCCHC2; p = 1.46 × 10-8; dependent SLE). A third locus upstream CYLC2 (rs12000047 and rs12005200, p < 2.00 × 10-8; dependent SLE) when the joint effect of the SNP main and GxE effects was considered. GWEIS gene-based tests identified: MTNR1B with GxE effect with dependent SLE in Generation Scotland; and PHF2 with the joint effect in UK Biobank (p < 2.77 × 10-6). Polygenic risk scores (PRSs) analyses incorporating GxE effects improved the prediction of depressive symptom scores, when using weights derived from either the UK Biobank GWAS of depressive symptoms (p = 0.01) or the PGC GWAS of major depressive disorder (p = 5.91 × 10-3). Using an independent sample, PRS derived using GWEIS GxE effects provided evidence of shared aetiologies between depressive symptoms and schizotypal personality, heart disease and COPD. Further such studies are required and may result in improved treatments for depression and other stress-related conditions.
Published: 2019

14. Integrated analysis of environmental and genetic influences on cord blood DNA methylation in new-borns

Author: Czamara, D, Eraslan, G, Page, CM, Lahti, J, Lahti-Pulkkinen, M, Hamalainen, E, Kajantie, E, Laivuori, H, Villa, PM, Reynolds, RM, Nystad, W, Haberg, SE, London, SJ, O'Donnell, KJ, Garg, E, Meaney, MJ, Entringer, S, Wadhwa, PD, Buss, C, Jones, MJ, Lin, DTS, MacIsaac, JL, Kobor, MS, Koen, N, Zar, HJ, Koenen, KC, Dalvie, S, Stein, DJ, Kondofersky, I, Mueller, NS, Theis, FJ, Raikkonen, K, Binder, EB, Wray, NR, Ripke, S, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Adams, MJ, Agerbo, E, Air, TM, Andlauer, TFM, Bacanu, S-A, Baekvad-Hansen, M, Beekman, ATF, Bigdeli, TB, Blackwood, DHR, Bryois, J, Buttenschon, HN, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Clarke, T-K, Coleman, JR, Colodro-Conde, L, Couvy-Duchesne, B, Craddock, N, Crawford, GE, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, Direk, N, Dolan, C, Dunn, EC, Eley, TC, Escott-Price, V, Kiadeh, FFH, Finucane, HK, Forstner, AJ, Frank, J, Gaspar, HA, Gill, M, Goes, FS, Gordon, SD, Grove, J, Hall, LS, Hansen, CS, Hansen, TF, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Horn, C, Hottenga, J-J, Hougaard, DM, Ising, M, Jansen, R, Jorgenson, E, Knowles, JA, Kohane, IS, Kraft, J, Kretzschmar, WW, Krogh, J, Kutalik, Z, Li, Y, Lind, PA, MacIntyre, DJ, MacKinnon, DF, Maier, RM, Maier, W, Marchini, J, Mbarek, H, McGrath, P, McGuffin, P, Medland, SE, Mehta, D, Middeldorp, CM, Mihailov, E, Milaneschi, Y, Milani, L, Mondimore, FM, Montgomery, GW, Mostafavi, S, Mullins, N, Nauck, M, Ng, B, Nivard, MG, Nyholt, DR, O'Reilly, PF, Oskarsson, H, Owen, MJ, Painter, JN, Pedersen, CB, Pedersen, MG, Peterson, RE, Pettersson, E, Peyrot, WJ, Pistis, G, Posthuma, D, Quiroz, JA, Qvist, P, Rice, JP, Riley, BP, Rivera, M, Mirza, SS, Schoevers, R, Schulte, EC, Shen, L, Shi, J, Shyn, S, Sigurdsson, E, Sinnamon, GCB, Smit, JH, Smith, DJ, Stefansson, H, Steinberg, S, Streit, F, Strohmaier, J, Tansey, KE, Teismann, H, Teumer, A, Thompson, W, Thomson, PA, Thorgeirsson, TE, Traylor, M, Treutlein, J, Trubetskoy, V, Uitterlinden, AG, Umbricht, D, Van der Auwera, S, van Hemert, AM, Viktorin, A, Visscher, PM, Wang, Y, Webb, BT, Weinsheimer, SM, Wellmann, J, Willemsen, G, Witt, SH, Wu, Y, Xi, HS, Yang, J, Zhang, F, Arolt, V, Baune, BT, Berger, K, Boomsma, D, Cichon, S, Dannlowski, U, de Geus, EJC, DePaulo, JR, Domenici, E, Domschke, K, Esko, T, Grabe, HJ, Hamilton, SP, Hayward, C, Heath, AC, Kendler, KS, Kloiber, S, Lewis, G, Li, QS, Lucae, S, Madden, PAF, Magnusson, PK, Martin, NG, McIntosh, AM, Metspalu, A, Mors, O, Mortensen, PB, Mueller-Myhsok, B, Nordentoft, M, Noethen, MM, O'Donovan, MC, Paciga, SA, Pedersen, NL, Penninx, BWJH, Perlis, RH, Porteous, DJ, Potash, JB, Preisig, M, Rietschel, M, Schaefer, C, Schulze, TG, Smoller, JW, Stefansson, K, Tiemeier, H, Uher, R, Voelzke, H, Weissman, MM, Werge, T, Lewis, CM, Levinson, DF, Breen, G, Borglum, AD, Sullivan, PF, Czamara, D, Eraslan, G, Page, CM, Lahti, J, Lahti-Pulkkinen, M, Hamalainen, E, Kajantie, E, Laivuori, H, Villa, PM, Reynolds, RM, Nystad, W, Haberg, SE, London, SJ, O'Donnell, KJ, Garg, E, Meaney, MJ, Entringer, S, Wadhwa, PD, Buss, C, Jones, MJ, Lin, DTS, MacIsaac, JL, Kobor, MS, Koen, N, Zar, HJ, Koenen, KC, Dalvie, S, Stein, DJ, Kondofersky, I, Mueller, NS, Theis, FJ, Raikkonen, K, Binder, EB, Wray, NR, Ripke, S, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Adams, MJ, Agerbo, E, Air, TM, Andlauer, TFM, Bacanu, S-A, Baekvad-Hansen, M, Beekman, ATF, Bigdeli, TB, Blackwood, DHR, Bryois, J, Buttenschon, HN, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Clarke, T-K, Coleman, JR, Colodro-Conde, L, Couvy-Duchesne, B, Craddock, N, Crawford, GE, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, Direk, N, Dolan, C, Dunn, EC, Eley, TC, Escott-Price, V, Kiadeh, FFH, Finucane, HK, Forstner, AJ, Frank, J, Gaspar, HA, Gill, M, Goes, FS, Gordon, SD, Grove, J, Hall, LS, Hansen, CS, Hansen, TF, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Horn, C, Hottenga, J-J, Hougaard, DM, Ising, M, Jansen, R, Jorgenson, E, Knowles, JA, Kohane, IS, Kraft, J, Kretzschmar, WW, Krogh, J, Kutalik, Z, Li, Y, Lind, PA, MacIntyre, DJ, MacKinnon, DF, Maier, RM, Maier, W, Marchini, J, Mbarek, H, McGrath, P, McGuffin, P, Medland, SE, Mehta, D, Middeldorp, CM, Mihailov, E, Milaneschi, Y, Milani, L, Mondimore, FM, Montgomery, GW, Mostafavi, S, Mullins, N, Nauck, M, Ng, B, Nivard, MG, Nyholt, DR, O'Reilly, PF, Oskarsson, H, Owen, MJ, Painter, JN, Pedersen, CB, Pedersen, MG, Peterson, RE, Pettersson, E, Peyrot, WJ, Pistis, G, Posthuma, D, Quiroz, JA, Qvist, P, Rice, JP, Riley, BP, Rivera, M, Mirza, SS, Schoevers, R, Schulte, EC, Shen, L, Shi, J, Shyn, S, Sigurdsson, E, Sinnamon, GCB, Smit, JH, Smith, DJ, Stefansson, H, Steinberg, S, Streit, F, Strohmaier, J, Tansey, KE, Teismann, H, Teumer, A, Thompson, W, Thomson, PA, Thorgeirsson, TE, Traylor, M, Treutlein, J, Trubetskoy, V, Uitterlinden, AG, Umbricht, D, Van der Auwera, S, van Hemert, AM, Viktorin, A, Visscher, PM, Wang, Y, Webb, BT, Weinsheimer, SM, Wellmann, J, Willemsen, G, Witt, SH, Wu, Y, Xi, HS, Yang, J, Zhang, F, Arolt, V, Baune, BT, Berger, K, Boomsma, D, Cichon, S, Dannlowski, U, de Geus, EJC, DePaulo, JR, Domenici, E, Domschke, K, Esko, T, Grabe, HJ, Hamilton, SP, Hayward, C, Heath, AC, Kendler, KS, Kloiber, S, Lewis, G, Li, QS, Lucae, S, Madden, PAF, Magnusson, PK, Martin, NG, McIntosh, AM, Metspalu, A, Mors, O, Mortensen, PB, Mueller-Myhsok, B, Nordentoft, M, Noethen, MM, O'Donovan, MC, Paciga, SA, Pedersen, NL, Penninx, BWJH, Perlis, RH, Porteous, DJ, Potash, JB, Preisig, M, Rietschel, M, Schaefer, C, Schulze, TG, Smoller, JW, Stefansson, K, Tiemeier, H, Uher, R, Voelzke, H, Weissman, MM, Werge, T, Lewis, CM, Levinson, DF, Breen, G, Borglum, AD, and Sullivan, PF
Abstract: Epigenetic processes, including DNA methylation (DNAm), are among the mechanisms allowing integration of genetic and environmental factors to shape cellular function. While many studies have investigated either environmental or genetic contributions to DNAm, few have assessed their integrated effects. Here we examine the relative contributions of prenatal environmental factors and genotype on DNA methylation in neonatal blood at variably methylated regions (VMRs) in 4 independent cohorts (overall n = 2365). We use Akaike's information criterion to test which factors best explain variability of methylation in the cohort-specific VMRs: several prenatal environmental factors (E), genotypes in cis (G), or their additive (G + E) or interaction (GxE) effects. Genetic and environmental factors in combination best explain DNAm at the majority of VMRs. The CpGs best explained by either G, G + E or GxE are functionally distinct. The enrichment of genetic variants from GxE models in GWAS for complex disorders supports their importance for disease risk.
Published: 2019

15. Applying polygenic risk scoring for psychiatric disorders to a large family with bipolar disorder and major depressive disorder

Author: de Jong, S, Diniz, MJA, Saloma, A, Gadelha, A, Santoro, ML, Ota, VK, Noto, C, Wray, NR, Ripke, S, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Adams, MJ, Agerbo, E, Air, TM, Andlauer, TFM, Bacanu, SA, Bækvad-Hansen, M, Beekman, ATF, Bigdeli, TB, Binder, EB, Blackwood, DHR, Bryois, J, Buttenschøn, HN, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Clarke, TK, Coleman, JRI, Colodro-Conde, L, Couvy-Duchesne, B, Craddock, N, Crawford, GE, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, Direk, N, Dolan, CV, Dunn, EC, Eley, TC, Escott-Price, V, Kiadeh, FFH, Finucane, HK, Forstner, AJ, Frank, J, Gaspar, HA, Gill, M, Goes, FS, Gordon, SD, Grove, J, Hansen, CS, Hansen, TF, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Horn, C, Hottenga, JJ, Hougaard, DM, Ising, M, Jansen, R, Jones, I, Jones, LA, Jorgenson, E, Knowles, JA, Kohane, IS, Kraft, J, Kretzschmar, WW, Krogh, J, Kutalik, Z, Li, Y, Lind, PA, MacIntyre, DJ, MacKinnon, DF, Maier, RM, Maier, W, Marchini, J, Mbarek, H, McGrath, P, McGuffin, P, Medland, SE, Mehta, D, Middeldorp, CM, Mihailov, E, Milaneschi, Y, Milani, L, Mondimore, FM, Montgomery, GW, Mostafavi, S, Mullins, N, Nauck, M, Ng, B, Nivard, MG, Nyholt, DR, Oskarsson, H, Owen, MJ, Painter, JN, de Jong, S, Diniz, MJA, Saloma, A, Gadelha, A, Santoro, ML, Ota, VK, Noto, C, Wray, NR, Ripke, S, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Adams, MJ, Agerbo, E, Air, TM, Andlauer, TFM, Bacanu, SA, Bækvad-Hansen, M, Beekman, ATF, Bigdeli, TB, Binder, EB, Blackwood, DHR, Bryois, J, Buttenschøn, HN, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Clarke, TK, Coleman, JRI, Colodro-Conde, L, Couvy-Duchesne, B, Craddock, N, Crawford, GE, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, Direk, N, Dolan, CV, Dunn, EC, Eley, TC, Escott-Price, V, Kiadeh, FFH, Finucane, HK, Forstner, AJ, Frank, J, Gaspar, HA, Gill, M, Goes, FS, Gordon, SD, Grove, J, Hansen, CS, Hansen, TF, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Horn, C, Hottenga, JJ, Hougaard, DM, Ising, M, Jansen, R, Jones, I, Jones, LA, Jorgenson, E, Knowles, JA, Kohane, IS, Kraft, J, Kretzschmar, WW, Krogh, J, Kutalik, Z, Li, Y, Lind, PA, MacIntyre, DJ, MacKinnon, DF, Maier, RM, Maier, W, Marchini, J, Mbarek, H, McGrath, P, McGuffin, P, Medland, SE, Mehta, D, Middeldorp, CM, Mihailov, E, Milaneschi, Y, Milani, L, Mondimore, FM, Montgomery, GW, Mostafavi, S, Mullins, N, Nauck, M, Ng, B, Nivard, MG, Nyholt, DR, Oskarsson, H, Owen, MJ, and Painter, JN
Abstract: Psychiatric disorders are thought to have a complex genetic pathology consisting of interplay of common and rare variation. Traditionally, pedigrees are used to shed light on the latter only, while here we discuss the application of polygenic risk scores to also highlight patterns of common genetic risk. We analyze polygenic risk scores for psychiatric disorders in a large pedigree (n ~ 260) in which 30% of family members suffer from major depressive disorder or bipolar disorder. Studying patterns of assortative mating and anticipation, it appears increased polygenic risk is contributed by affected individuals who married into the family, resulting in an increasing genetic risk over generations. This may explain the observation of anticipation in mood disorders, whereby onset is earlier and the severity increases over the generations of a family. Joint analyses of rare and common variation may be a powerful way to understand the familial genetics of psychiatric disorders.
Published: 2018

16. Analysis of the influence of microRNAs in lithium response in bipolar disorder

Author: Reinbold, CS, Forstner, AJ, Hecker, J, Fullerton, JM, Hoffmann, P, Hou, L, Heilbronner, U, Degenhardt, F, Adli, M, Akiyama, K, Akula, N, Ardau, R, Arias, B, Backlund, L, Benabarre, A, Bengesser, S, Bhattacharjee, AK, Biernacka, JM, Birner, A, Marie-Claire, C, Cervantes, P, Chen, GB, Chen, HC, Chillotti, C, Clark, SR, Colom, F, Cousins, DA, Cruceanu, C, Czerski, PM, Dayer, A, Étain, B, Falkai, P, Frisén, L, Gard, S, Garnham, JS, Goes, FS, Grof, P, Gruber, O, Hashimoto, R, Hauser, J, Herms, S, Jamain, S, Jiménez, E, Kahn, JP, Kassem, L, Kittel-Schneider, S, Kliwicki, S, König, B, Kusumi, I, Lackner, N, Laje, G, Landén, M, Lavebratt, C, Leboyer, M, Leckband, SG, Jaramillo, CAL, MacQueen, G, Manchia, M, Martinsson, L, Mattheisen, M, McCarthy, MJ, McElroy, SL, Mitjans, M, Mondimore, FM, Monteleone, P, Nievergelt, CM, Ösby, U, Ozaki, N, Perlis, RH, Pfennig, A, Reich-Erkelenz, D, Rouleau, GA, Schofield, PR, Schubert, KO, Schweizer, BW, Seemüller, F, Severino, G, Shekhtman, T, Shilling, PD, Shimoda, K, Simhandl, C, Slaney, CM, Smoller, JW, Squassina, A, Stamm, TJ, Stopkova, P, Tighe, SK, Tortorella, A, Turecki, G, Volkert, J, Witt, SH, Wright, AJ, Trevor Young, L, Zandi, PP, Potash, JB, DePaulo, JR, Bauer, M, Reininghaus, E, Novák, T, Aubry, JM, Reinbold, CS, Forstner, AJ, Hecker, J, Fullerton, JM, Hoffmann, P, Hou, L, Heilbronner, U, Degenhardt, F, Adli, M, Akiyama, K, Akula, N, Ardau, R, Arias, B, Backlund, L, Benabarre, A, Bengesser, S, Bhattacharjee, AK, Biernacka, JM, Birner, A, Marie-Claire, C, Cervantes, P, Chen, GB, Chen, HC, Chillotti, C, Clark, SR, Colom, F, Cousins, DA, Cruceanu, C, Czerski, PM, Dayer, A, Étain, B, Falkai, P, Frisén, L, Gard, S, Garnham, JS, Goes, FS, Grof, P, Gruber, O, Hashimoto, R, Hauser, J, Herms, S, Jamain, S, Jiménez, E, Kahn, JP, Kassem, L, Kittel-Schneider, S, Kliwicki, S, König, B, Kusumi, I, Lackner, N, Laje, G, Landén, M, Lavebratt, C, Leboyer, M, Leckband, SG, Jaramillo, CAL, MacQueen, G, Manchia, M, Martinsson, L, Mattheisen, M, McCarthy, MJ, McElroy, SL, Mitjans, M, Mondimore, FM, Monteleone, P, Nievergelt, CM, Ösby, U, Ozaki, N, Perlis, RH, Pfennig, A, Reich-Erkelenz, D, Rouleau, GA, Schofield, PR, Schubert, KO, Schweizer, BW, Seemüller, F, Severino, G, Shekhtman, T, Shilling, PD, Shimoda, K, Simhandl, C, Slaney, CM, Smoller, JW, Squassina, A, Stamm, TJ, Stopkova, P, Tighe, SK, Tortorella, A, Turecki, G, Volkert, J, Witt, SH, Wright, AJ, Trevor Young, L, Zandi, PP, Potash, JB, DePaulo, JR, Bauer, M, Reininghaus, E, Novák, T, and Aubry, JM
Abstract: Bipolar disorder (BD) is a common, highly heritable neuropsychiatric disease characterized by recurrent episodes of mania and depression. Lithium is the best-established long-term treatment for BD, even though individual response is highly variable. Evidence suggests that some of this variability has a genetic basis. This is supported by the largest genome-wide association study (GWAS) of lithium response to date conducted by the International Consortium on Lithium Genetics (ConLiGen). Recently, we performed the first genome-wide analysis of the involvement of miRNAs in BD and identified nine BD-associated miRNAs. However, it is unknown whether these miRNAs are also associated with lithium response in BD. In the present study, we therefore tested whether common variants at these nine candidate miRNAs contribute to the variance in lithium response in BD. Furthermore, we systematically analyzed whether any other miRNA in the genome is implicated in the response to lithium. For this purpose, we performed gene-based tests for all known miRNA coding genes in the ConLiGen GWAS dataset (n = 2,563 patients) using a set-based testing approach adapted from the versatile gene-based test for GWAS (VEGAS2). In the candidate approach, miR-499a showed a nominally significant association with lithium response, providing some evidence for involvement in both development and treatment of BD. In the genome-wide miRNA analysis, 71 miRNAs showed nominally significant associations with the dichotomous phenotype and 106 with the continuous trait for treatment response. A total of 15 miRNAs revealed nominal significance in both phenotypes with miR-633 showing the strongest association with the continuous trait (p = 9.80E-04) and miR-607 with the dichotomous phenotype (p = 5.79E-04). No association between miRNAs and treatment response to lithium in BD in either of the tested conditions withstood multiple testing correction. Given the limited power of our study, the investigation of miRNAs
Published: 2018

17. Association of polygenic score for schizophrenia and HLA antigen and inflammation genes with response to lithium in bipolar affective disorder: A genome-wide association study

Author: Amare, AT, Schubert, KO, Hou, L, Clark, SR, Papiol, S, Heilbronner, U, Degenhardt, F, Tekola-Ayele, F, Hsu, YH, Shekhtman, T, Adli, M, Akula, N, Akiyama, K, Ardau, R, Arias, B, Aubry, JM, Backlund, L, Bhattacharjee, AK, Bellivier, F, Benabarre, A, Bengesser, S, Biernacka, JM, Birner, A, Brichant-Petitjean, C, Cervantes, P, Chen, HC, Chillotti, C, Cichon, S, Cruceanu, C, Czerski, PM, Dalkner, N, Dayer, A, Del Zompo, M, DePaulo, JR, Étain, B, Falkai, P, Forstner, AJ, Frisen, L, Frye, MA, Fullerton, JM, Gard, S, Garnham, JS, Goes, FS, Grigoroiu-Serbanescu, M, Grof, P, Hashimoto, R, Hauser, J, Herms, S, Hoffmann, P, Hofmann, A, Jamain, S, Jiménez, E, Kahn, JP, Kassem, L, Kuo, PH, Kato, T, Kelsoe, J, Kittel-Schneider, S, Kliwicki, S, König, B, Kusumi, I, Laje, G, Landén, M, Lavebratt, C, Leboyer, M, Leckband, SG, Tortorella, A, Manchia, M, Martinsson, L, McCarthy, MJ, McElroy, S, Colom, F, Mitjans, M, Mondimore, FM, Monteleone, P, Nievergelt, CM, Nöthen, MM, Novák, T, O'Donovan, C, Ozaki, N, Ösby, U, Pfennig, A, Potash, JB, Reif, A, Reininghaus, E, Rouleau, GA, Rybakowski, JK, Schalling, M, Schofield, PR, Schweizer, BW, Severino, G, Shilling, PD, Shimoda, K, Simhandl, C, Slaney, CM, Squassina, A, Stamm, T, Stopkova, P, Maj, M, Turecki, G, Amare, AT, Schubert, KO, Hou, L, Clark, SR, Papiol, S, Heilbronner, U, Degenhardt, F, Tekola-Ayele, F, Hsu, YH, Shekhtman, T, Adli, M, Akula, N, Akiyama, K, Ardau, R, Arias, B, Aubry, JM, Backlund, L, Bhattacharjee, AK, Bellivier, F, Benabarre, A, Bengesser, S, Biernacka, JM, Birner, A, Brichant-Petitjean, C, Cervantes, P, Chen, HC, Chillotti, C, Cichon, S, Cruceanu, C, Czerski, PM, Dalkner, N, Dayer, A, Del Zompo, M, DePaulo, JR, Étain, B, Falkai, P, Forstner, AJ, Frisen, L, Frye, MA, Fullerton, JM, Gard, S, Garnham, JS, Goes, FS, Grigoroiu-Serbanescu, M, Grof, P, Hashimoto, R, Hauser, J, Herms, S, Hoffmann, P, Hofmann, A, Jamain, S, Jiménez, E, Kahn, JP, Kassem, L, Kuo, PH, Kato, T, Kelsoe, J, Kittel-Schneider, S, Kliwicki, S, König, B, Kusumi, I, Laje, G, Landén, M, Lavebratt, C, Leboyer, M, Leckband, SG, Tortorella, A, Manchia, M, Martinsson, L, McCarthy, MJ, McElroy, S, Colom, F, Mitjans, M, Mondimore, FM, Monteleone, P, Nievergelt, CM, Nöthen, MM, Novák, T, O'Donovan, C, Ozaki, N, Ösby, U, Pfennig, A, Potash, JB, Reif, A, Reininghaus, E, Rouleau, GA, Rybakowski, JK, Schalling, M, Schofield, PR, Schweizer, BW, Severino, G, Shilling, PD, Shimoda, K, Simhandl, C, Slaney, CM, Squassina, A, Stamm, T, Stopkova, P, Maj, M, and Turecki, G
Abstract: IMPORTANCE Lithium is a first-line mood stabilizer for the treatment of bipolar affective disorder (BPAD). However, the efficacy of lithium varies widely, with a nonresponse rate of up to 30%. Biological response markers are lacking. Genetic factors are thought to mediate treatment response to lithium, and there is a previously reported genetic overlap between BPAD and schizophrenia (SCZ). OBJECTIVES To test whether a polygenic score for SCZ is associated with treatment response to lithium in BPAD and to explore the potential molecular underpinnings of this association. DESIGN, SETTING, AND PARTICIPANTS A total of 2586 patients with BPAD who had undergone lithium treatment were genotyped and assessed for long-term response to treatment between 2008 and 2013.Weighted SCZ polygenic scores were computed at different P value thresholds using summary statistics from an international multicenter genome-wide association study (GWAS) of 36 989 individuals with SCZ and genotype data from patients with BPAD from the Consortium on Lithium Genetics. For functional exploration, a cross-trait meta-GWAS and pathway analysis was performed, combining GWAS summary statistics on SCZ and response to treatment with lithium. Data analysis was performed from September 2016 to February 2017. MAIN OUTCOMES AND MEASURES Treatment response to lithiumwas defined on both the categorical and continuous scales using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder score. The effect measures include odds ratios and the proportion of variance explained. RESULTS Of the 2586 patients in the study (mean [SD] age, 47.2 [13.9] years), 1478 were women and 1108 were men. The polygenic score for SCZ was inversely associated with lithium treatment response in the categorical outcome, at a threshold P < 5 ? 10-2. Patients with BPAD who had a low polygenic load for SCZ responded better to lithium, with odds ratios for lithium response ranging from 3.46 (95%
Published: 2018

18. Genetic variants associated with response to lithium treatment in bipolar disorder: A genome-wide association study

Author: Hou, L, Heilbronner, U, Degenhardt, F, Adli, M, Akiyama, K, Akula, N, Ardau, R, Arias, B, Backlund, L, Banzato, CEM, Benabarre, A, Bengesser, S, Bhattacharjee, AK, Biernacka, JM, Birner, A, Brichant-Petitjean, C, Bui, ET, Cervantes, P, Chen, GB, Chen, HC, Chillotti, C, Cichon, S, Clark, SR, Colom, F, Cousins, DA, Cruceanu, C, Czerski, PM, Dantas, CR, Dayer, A, Étain, B, Falkai, P, Forstner, AJ, Frisén, L, Fullerton, JM, Gard, S, Garnham, JS, Goes, FS, Grof, P, Gruber, O, Hashimoto, R, Hauser, J, Herms, S, Hoffmann, P, Hofmann, A, Jamain, S, Jiménez, E, Kahn, JP, Kassem, L, Kittel-Schneider, S, Kliwicki, S, König, B, Kusumi, I, Lackner, N, Laje, G, Landén, M, Lavebratt, C, Leboyer, M, Leckband, SG, Jaramillo, CAL, Macqueen, G, Manchia, M, Martinsson, L, Mattheisen, M, McCarthy, MJ, McElroy, SL, Mitjans, M, Mondimore, FM, Monteleone, P, Nievergelt, CM, Nöthen, MM, Ösby, U, Ozaki, N, Perlis, RH, Pfennig, A, Reich-Erkelenz, D, Rouleau, GA, Schofield, PR, Schubert, KO, Schweizer, BW, Seemüller, F, Severino, G, Shekhtman, T, Shilling, PD, Shimoda, K, Simhandl, C, Slaney, CM, Smoller, JW, Squassina, A, Stamm, T, Stopkova, P, Tighe, SK, Tortorella, A, Turecki, G, Volkert, J, Witt, S, Wright, A, Young, LT, Zandi, PP, Potash, JB, Depaulo, JR, Hou, L, Heilbronner, U, Degenhardt, F, Adli, M, Akiyama, K, Akula, N, Ardau, R, Arias, B, Backlund, L, Banzato, CEM, Benabarre, A, Bengesser, S, Bhattacharjee, AK, Biernacka, JM, Birner, A, Brichant-Petitjean, C, Bui, ET, Cervantes, P, Chen, GB, Chen, HC, Chillotti, C, Cichon, S, Clark, SR, Colom, F, Cousins, DA, Cruceanu, C, Czerski, PM, Dantas, CR, Dayer, A, Étain, B, Falkai, P, Forstner, AJ, Frisén, L, Fullerton, JM, Gard, S, Garnham, JS, Goes, FS, Grof, P, Gruber, O, Hashimoto, R, Hauser, J, Herms, S, Hoffmann, P, Hofmann, A, Jamain, S, Jiménez, E, Kahn, JP, Kassem, L, Kittel-Schneider, S, Kliwicki, S, König, B, Kusumi, I, Lackner, N, Laje, G, Landén, M, Lavebratt, C, Leboyer, M, Leckband, SG, Jaramillo, CAL, Macqueen, G, Manchia, M, Martinsson, L, Mattheisen, M, McCarthy, MJ, McElroy, SL, Mitjans, M, Mondimore, FM, Monteleone, P, Nievergelt, CM, Nöthen, MM, Ösby, U, Ozaki, N, Perlis, RH, Pfennig, A, Reich-Erkelenz, D, Rouleau, GA, Schofield, PR, Schubert, KO, Schweizer, BW, Seemüller, F, Severino, G, Shekhtman, T, Shilling, PD, Shimoda, K, Simhandl, C, Slaney, CM, Smoller, JW, Squassina, A, Stamm, T, Stopkova, P, Tighe, SK, Tortorella, A, Turecki, G, Volkert, J, Witt, S, Wright, A, Young, LT, Zandi, PP, Potash, JB, and Depaulo, JR
Abstract: Background Lithium is a first-line treatment in bipolar disorder, but individual response is variable. Previous studies have suggested that lithium response is a heritable trait. However, no genetic markers of treatment response have been reproducibly identified. Methods Here, we report the results of a genome-wide association study of lithium response in 2563 patients collected by 22 participating sites from the International Consortium on Lithium Genetics (ConLiGen). Data from common single nucleotide polymorphisms (SNPs) were tested for association with categorical and continuous ratings of lithium response. Lithium response was measured using a well established scale (Alda scale). Genotyped SNPs were used to generate data at more than 6 million sites, using standard genomic imputation methods. Traits were regressed against genotype dosage. Results were combined across two batches by meta-analysis. Findings A single locus of four linked SNPs on chromosome 21 met genome-wide significance criteria for association with lithium response (rs79663003, p=1·37×10-8; rs78015114, p=1·31×10-8; rs74795342, p=3·31×10-9; and rs75222709, p=3·50×10-9). In an independent, prospective study of 73 patients treated with lithium monotherapy for a period of up to 2 years, carriers of the response-associated alleles had a significantly lower rate of relapse than carriers of the alternate alleles (p=0·03268, hazard ratio 3·8, 95% CI 1·1-13·0). Interpretation The response-associated region contains two genes for long, non-coding RNAs (lncRNAs), AL157359.3 and AL157359.4. LncRNAs are increasingly appreciated as important regulators of gene expression, particularly in the CNS. Confirmed biomarkers of lithium response would constitute an important step forward in the clinical management of bipolar disorder. Further studies are needed to establish the biological context and potential clinical utility of these findings. Funding Deutsche Forschungsgemeinschaft, National Institute of Mental Hea
Published: 2016

19. Genome-wide association study of 40,000 individuals identifies two novel loci associated with bipolar disorder

Author: Hou, L, Bergen, SE, Akula, N, Song, J, Hultman, CM, Landén, M, Adli, M, Alda, M, Ardau, R, Arias, B, Aubry, JM, Backlund, L, Badner, JA, Barrett, TB, Bauer, M, Baune, BT, Bellivier, F, Benabarre, A, Bengesser, S, Berrettini, WH, Bhattacharjee, AK, Biernacka, JM, Birner, A, Bloss, CS, Brichant-Petitjean, C, Bui, ET, Byerley, W, Cervantes, P, Chillotti, C, Cichon, S, Colom, F, Coryell, W, Craig, DW, Cruceanu, C, Czerski, PM, Davis, T, Dayer, A, Degenhardt, F, Del Zompo, M, DePaulo, JR, Edenberg, HJ, Étain, B, Falkai, P, Foroud, T, Forstner, AJ, Frisén, L, Frye, MA, Fullerton, JM, Gard, S, Garnham, JS, Gershon, ES, Goes, FS, Greenwood, TA, Grigoroiu-Serbanescu, M, Hauser, J, Heilbronner, U, Heilmann-Heimbach, S, Herms, S, Hipolito, M, Hitturlingappa, S, Hoffmann, P, Hofmann, A, Jamain, S, Jiménez, E, Kahn, JP, Kassem, L, Kelsoe, JR, Kittel-Schneider, S, Kliwicki, S, Koller, DL, König, B, Lackner, N, Laje, G, Lang, M, Lavebratt, C, Lawson, WB, Leboyer, M, Leckband, SG, Liu, C, Maaser, A, Mahon, PB, Maier, W, Maj, M, Manchia, M, Martinsson, L, McCarthy, MJ, McElroy, SL, McInnis, MG, McKinney, R, Mitchell, PB, Mitjans, M, Mondimore, FM, Monteleone, P, Mühleisen, TW, Nievergelt, CM, Nöthen, MM, Novák, T, Nurnberger, JI, Nwulia, EA, Ösby, U, Hou, L, Bergen, SE, Akula, N, Song, J, Hultman, CM, Landén, M, Adli, M, Alda, M, Ardau, R, Arias, B, Aubry, JM, Backlund, L, Badner, JA, Barrett, TB, Bauer, M, Baune, BT, Bellivier, F, Benabarre, A, Bengesser, S, Berrettini, WH, Bhattacharjee, AK, Biernacka, JM, Birner, A, Bloss, CS, Brichant-Petitjean, C, Bui, ET, Byerley, W, Cervantes, P, Chillotti, C, Cichon, S, Colom, F, Coryell, W, Craig, DW, Cruceanu, C, Czerski, PM, Davis, T, Dayer, A, Degenhardt, F, Del Zompo, M, DePaulo, JR, Edenberg, HJ, Étain, B, Falkai, P, Foroud, T, Forstner, AJ, Frisén, L, Frye, MA, Fullerton, JM, Gard, S, Garnham, JS, Gershon, ES, Goes, FS, Greenwood, TA, Grigoroiu-Serbanescu, M, Hauser, J, Heilbronner, U, Heilmann-Heimbach, S, Herms, S, Hipolito, M, Hitturlingappa, S, Hoffmann, P, Hofmann, A, Jamain, S, Jiménez, E, Kahn, JP, Kassem, L, Kelsoe, JR, Kittel-Schneider, S, Kliwicki, S, Koller, DL, König, B, Lackner, N, Laje, G, Lang, M, Lavebratt, C, Lawson, WB, Leboyer, M, Leckband, SG, Liu, C, Maaser, A, Mahon, PB, Maier, W, Maj, M, Manchia, M, Martinsson, L, McCarthy, MJ, McElroy, SL, McInnis, MG, McKinney, R, Mitchell, PB, Mitjans, M, Mondimore, FM, Monteleone, P, Mühleisen, TW, Nievergelt, CM, Nöthen, MM, Novák, T, Nurnberger, JI, Nwulia, EA, and Ösby, U
Abstract: Bipolar disorder (BD) is a genetically complex mental illness characterized by severe oscillations of mood and behaviour. Genome-wide association studies (GWAS) have identified several risk loci that together account for a small portion of the heritability. To identify additional risk loci, we performed a two-stage meta-analysis of > 9 million genetic variants in 9,784 bipolar disorder patients and 30,471 controls, the largest GWAS of BD to date. In this study, to increase power we used ~2,000 lithium-treated cases with a long-term diagnosis of BD from the Consortium on Lithium Genetics, excess controls, and analytic methods optimized for markers on the X-chromosome. In addition to four known loci, results revealed genome-wide significant associations at two novel loci: an intergenic region on 9p21.3 (rs12553324, P= 5.87×10-9; odds ratio (OR)=1.12) and markers within ERBB2 (rs2517959, P= 4.53×10-9; OR=1.13). No significant X-chromosome associations were detected and Xlinked markers explained very little BD heritability. The results add to a growing list of common autosomal variants involved in BD and illustrate the power of comparing well-characterized cases to an excess of controls in GWAS.
Published: 2016

20. Assessment of Response to Lithium Maintenance Treatment in Bipolar Disorder: A Consortium on Lithium Genetics (ConLiGen) Report

Author: Manchia, M, Adli, M, Akula, N, Ardau, R, Aubry, JM, Backlund, L, Banzato, CEM, Baune, BT, Bellivier, F, Bengesser, S, Biernacka, JM, Brichant-Petitjean, C, Bui, E, Calkin, CV, Cheng, ATA, Chillotti, C, Cichon, S, Clark, S, Czerski, PM, Dantas, C, Del Zompo, M, DePaulo, JR, Detera-Wadleigh, SD, Etain, B, Falkai, P, Frisén, L, Frye, MA, Fullerton, J, Gard, S, Garnham, J, Goes, FS, Grof, P, Gruber, O, Hashimoto, R, Hauser, J, Heilbronner, U, Hoban, R, Hou, L, Jamain, S, Kahn, JP, Kassem, L, Kato, T, Kelsoe, JR, Kittel-Schneider, S, Kliwicki, S, Kuo, PH, Kusumi, I, Laje, G, Lavebratt, C, Leboyer, M, Leckband, SG, López Jaramillo, CA, Maj, M, Malafosse, A, Martinsson, L, Masui, T, Mitchell, PB, Mondimore, F, Monteleone, P, Nallet, A, Neuner, M, Novák, T, O'Donovan, C, Ösby, U, Ozaki, N, Perlis, RH, Pfennig, A, Potash, JB, Reich-Erkelenz, D, Reif, A, Reininghaus, E, Richardson, S, Rouleau, GA, Rybakowski, JK, Schalling, M, Schofield, PR, Schubert, OK, Schweizer, B, Seemüller, F, Grigoroiu-Serbanescu, M, Severino, G, Seymour, LR, Slaney, C, Smoller, JW, Squassina, A, Stamm, T, Steele, J, Stopkova, P, Tighe, SK, Tortorella, A, Turecki, G, Wray, NR, Wright, A, Zandi, PP, Zilles, D, Bauer, M, Rietschel, M, McMahon, FJ, Schulze, TG, Alda, M, Manchia, M, Adli, M, Akula, N, Ardau, R, Aubry, JM, Backlund, L, Banzato, CEM, Baune, BT, Bellivier, F, Bengesser, S, Biernacka, JM, Brichant-Petitjean, C, Bui, E, Calkin, CV, Cheng, ATA, Chillotti, C, Cichon, S, Clark, S, Czerski, PM, Dantas, C, Del Zompo, M, DePaulo, JR, Detera-Wadleigh, SD, Etain, B, Falkai, P, Frisén, L, Frye, MA, Fullerton, J, Gard, S, Garnham, J, Goes, FS, Grof, P, Gruber, O, Hashimoto, R, Hauser, J, Heilbronner, U, Hoban, R, Hou, L, Jamain, S, Kahn, JP, Kassem, L, Kato, T, Kelsoe, JR, Kittel-Schneider, S, Kliwicki, S, Kuo, PH, Kusumi, I, Laje, G, Lavebratt, C, Leboyer, M, Leckband, SG, López Jaramillo, CA, Maj, M, Malafosse, A, Martinsson, L, Masui, T, Mitchell, PB, Mondimore, F, Monteleone, P, Nallet, A, Neuner, M, Novák, T, O'Donovan, C, Ösby, U, Ozaki, N, Perlis, RH, Pfennig, A, Potash, JB, Reich-Erkelenz, D, Reif, A, Reininghaus, E, Richardson, S, Rouleau, GA, Rybakowski, JK, Schalling, M, Schofield, PR, Schubert, OK, Schweizer, B, Seemüller, F, Grigoroiu-Serbanescu, M, Severino, G, Seymour, LR, Slaney, C, Smoller, JW, Squassina, A, Stamm, T, Steele, J, Stopkova, P, Tighe, SK, Tortorella, A, Turecki, G, Wray, NR, Wright, A, Zandi, PP, Zilles, D, Bauer, M, Rietschel, M, McMahon, FJ, Schulze, TG, and Alda, M
Abstract: Objective:The assessment of response to lithium maintenance treatment in bipolar disorder (BD) is complicated by variable length of treatment, unpredictable clinical course, and often inconsistent compliance. Prospective and retrospective methods of assessment of lithium response have been proposed in the literature. In this study we report the key phenotypic measures of the "Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder" scale currently used in the Consortium on Lithium Genetics (ConLiGen) study.Materials and Methods:Twenty-nine ConLiGen sites took part in a two-stage case-vignette rating procedure to examine inter-rater agreement [Kappa (κ)] and reliability [intra-class correlation coefficient (ICC)] of lithium response. Annotated first-round vignettes and rating guidelines were circulated to expert research clinicians for training purposes between the two stages. Further, we analyzed the distributional properties of the treatment response scores available for 1,308 patients using mixture modeling.Results:Substantial and moderate agreement was shown across sites in the first and second sets of vignettes (κ = 0.66 and κ = 0.54, respectively), without significant improvement from training. However, definition of response using the A score as a quantitative trait and selecting cases with B criteria of 4 or less showed an improvement between the two stages (ICC1 = 0.71 and ICC2 = 0.75, respectively). Mixture modeling of score distribution indicated three subpopulations (full responders, partial responders, non responders).Conclusions:We identified two definitions of lithium response, one dichotomous and the other continuous, with moderate to substantial inter-rater agreement and reliability. Accurate phenotypic measurement of lithium response is crucial for the ongoing ConLiGen pharmacogenomic study.
Published: 2013

21. Mood-incongruent psychotic features in bipolar disorder: familial aggregation and suggestive linkage to 2p11-q14 and 13q21-33.

Author: Goes FS, Zandi PP, Miao K, McMahon FJ, Steele J, Willour VL, MacKinnon DF, Mondimore FM, Schweizer B, Nurnberger JI Jr., Rice JP, Scheftner W, Coryell W, Berrettini WH, Kelsoe JR, Byerley W, Murphy DL, Gershon ES, DePaulo JR Jr., and McInnis MG
Abstract: Objective: Mood-incongruent psychotic features in bipolar disorder may signify a more severe form of the illness and might represent phenotypic manifestations of susceptibility genes shared with schizophrenia. This study attempts to characterize clinical correlates, familial aggregation, and genetic linkage in subjects with these features.Method: Subjects were drawn from The National Institute of Mental Health (NIMH) Genetics Initiative Bipolar Disorder Collaborative cohort, consisting of 708 families recruited at 10 academic medical centers. Subjects with mood-incongruent and mood-congruent psychotic features were compared on clinical variables. Familial aggregation was tested using a proband-predictive model and generalized estimating equations. A genome-wide linkage scan incorporating a mood-incongruence covariate was performed.Results: Mood-incongruent psychotic features were associated with an increased rate of hospitalization and attempted suicide. A proband with mood-incongruence predicted mood-incongruence in relatives with bipolar I disorder when compared with all other subjects and when compared with subjects with mood-congruent psychosis. The presence of mood-incongruent psychotic features increased evidence for linkage on chromosomes 13q21-33 and 2p11-q14. These logarithm of the odds ratio (LOD) scores and their increase from baseline met empirical genome-wide suggestive criteria for significance.Conclusions: Mood-incongruent psychotic features showed evidence of a more severe course, familial aggregation, and suggestive linkage to two chromosomal regions previously implicated in major mental illness susceptibility. The 13q21-33 finding supports prior evidence of bipolar disorder/schizophrenia overlap in this region, while the 2p11-q14 finding is, to the authors' knowledge, the first to suggest that this schizophrenia linkage region might also harbor a bipolar disorder susceptibility gene. [ABSTRACT FROM AUTHOR]
Published: 2007
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22. Whole-exome sequencing of 81 individuals from 27 multiply affected bipolar disorder families

Author: Fermín Mayoral, Fabio Rivas, Jesus Haro González, Franziska Degenhardt, Julian Hecker, Fermin Perez Perez, Marcella Rietschel, Michael Bauer, Margot Albus, Markus M. Nöthen, Sascha B. Fischer, Susana Gil Flores, Francisco del Río Noriega, Mehdi Pirooznia, Stefan Herms, Jana Strohmaier, Stephanie H. Witt, Fernando S. Goes, Margitta Borrmann-Hassenbach, Anna Maaser-Hecker, Sugirthan Sivalingam, Sven Cichon, Lorena M. Schenk, Georg Auburger, Andreas Reif, Fabian Streit, María González, Francisco J. Cabaleiro Fabeiro, Peter Nürnberg, Jose Guzman-Parra, Andreas J. Forstner, Holger Thiele, Guillermo Orozco Diaz, Andrea Pfennig, Céline S. Reinbold, Johannes Schumacher, Per Hoffmann, [Forstner,AJ, Schumacher,J] Centre for Human Genetics, University of Marburg, Marburg, Germany. [Forstner,AJ, Schenk,LM, Maaser-Hecker,A, Sivalingam,S, Degenhardt,F, Schumacher,J, Herms,S, Hoffmann,P, Nöthen,MM, Cichon,S] Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany. [Forstner,AJ, Fischer,SB, Reinbold,CS, Cichon,S] Department of Biomedicine, University of Basel, Basel, Switzerland. [Forstner,AJ] Department of Psychiatry (UPK), University of Basel, Basel, Switzerland. [Fischer,SB, Cichon,S] Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland. [Strohmaier,J, Streit,F, Witt,SH, Rietschel,M] Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany. [Strohmaier,J] SRH University Heidelberg, Academy for Psychotherapy, Heidelberg, Germany. [Reinbold,CS] Center for Lifespan Changes in Brain and Cognition (LCBC), Department of Psychology, University of Oslo, Oslo, Norway. [Hecker,J] Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA. [Thiele,H, Nürnberg,P] Cologne Center for Genomics, University of Cologne, Cologne, Germany. [Guzman-Parra,J, González,MJ] Department of Mental Health, University Regional Hospital of Málaga, Institute of Biomedicine of Málaga (IBIMA), Málaga, Spain. [Orozco Diaz,G] Unidad de Gestión Clínica del Dispositivo de Cuidados Críticos y Urgencias del Distrito Sanitario Málaga - Coin- Gudalhorce, Málaga, Spain. [Auburger,G] Experimental Neurology, Department of Neurology, Goethe University Hospital, Frankfurt am Main, Germany. [Albus,M, Borrmann-Hassenbach,M]Isar Amper Klinikum München Ost, kbo, Haar, Germany. [Gil Flores,S] Department of Mental Health, University Hospital of Reina Sofia, Cordoba, Spain. [Cabaleiro Fabeiro,FJ] Department of Mental Health, Hospital of Jaén, Jaén, Spain. [del Río Noriega,F] Department of Mental Health, Hospital of Jerez de la Frontera, Jerez de la Frontera, Spain. [Perez Perez,F] Department of Mental Health, Hospital of Puerto Real, Cádiz, Spain. [Haro González,J] Department of Mental Health, Hospital Punta de Europa, Algeciras, Spain. [Rivas,F, Mayoral,F] Department of Psychiatry, Carlos Haya Regional University Hospital, Malaga, Spain. [Bauer,M, Pfennig,A] Department of Psychiatry and Psychotherapy, Medical Faculty, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany. [Reif,A] Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt am Main, Frankfurt am Main, Germany. [Hoffmann,P, Cichon,S] Institute of Neuroscience and Medicine (INM-1), Research Center Jülich, Jülich, Germany. [Pirooznia,M, Goes,FS] Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA, The study was supported by the German Federal Ministry of Education and Research (BMBF) through the Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders), under the auspices of the e:Med Programme (grant 01ZX1314A/01ZX1614A to M.M.N. Forstner et al. Translational Psychiatry (2020) 10:57 Page 8 of 10 and S.C., grant 01ZX1314G/01ZX1614G to M.R.) and through ERA-NET NEURON, 'SynSchiz—Linking synaptic dysfunction to disease mechanisms in schizophrenia—a multilevel investigation' (01EW1810 to MR). The study was also supported by the German Research Foundation (DFG, grant FOR2107, RI908/11-1 and RI908/11–2 to M.R., and NO246/10-1 and NO 246/10-2 to M.M.N.), and the Swiss National Science Foundation (SNSF, grant 156791 to S.C.). M.M.N. is a member of the DFG-funded Excellence-Cluster ImmunoSensation.
Subjects: Candidate gene, Bipolar Disorder, Psychiatry and Psychology::Mental Disorders::Mood Disorders::Affective Disorders, Psychotic::Bipolar Disorder [Medical Subject Headings], Neuropsiquiatría, Disease, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], 0302 clinical medicine, Germany, Exome, Exome sequencing, Genetics, 0303 health sciences, Trastorno bipolar, Predisposición genética a la enfermedad, Neuropsychiatry, Phenomena and Processes::Genetic Phenomena::Genotype::Genetic Predisposition to Disease [Medical Subject Headings], 3. Good health, Pedigree, Psychiatry and Mental health, Schizophrenia, Phenomena and Processes::Genetic Phenomena::Inheritance Patterns::Penetrance [Medical Subject Headings], Psychiatry and Psychology::Mental Disorders::Mental Disorders Diagnosed in Childhood::Child Development Disorders, Pervasive::Autistic Disorder [Medical Subject Headings], Biology, Molecular neuroscience, Article, Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Exome [Medical Subject Headings], lcsh:RC321-571, 03 medical and health sciences, Cellular and Molecular Neuroscience, Exome Sequencing, medicine, Psychiatry and Psychology::Mental Disorders::Schizophrenia and Disorders with Psychotic Features::Schizophrenia [Medical Subject Headings], Humans, Genetic Predisposition to Disease, Bipolar disorder, ddc:610, Allele, Gene, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Biological Psychiatry, 030304 developmental biology, Geographical Locations::Geographic Locations::Europe::Spain [Medical Subject Headings], Secuenciación del exoma completo, Whole exome sequencing, Anatomy::Nervous System::Central Nervous System::Brain [Medical Subject Headings], medicine.disease, Geographical Locations::Geographic Locations::Europe::Germany [Medical Subject Headings], Autism, 030217 neurology & neurosurgery, RGS Proteins
Abstract: Bipolar disorder (BD) is a highly heritable neuropsychiatric disease characterized by recurrent episodes of depression and mania. Research suggests that the cumulative impact of common alleles explains 25–38% of phenotypic variance, and that rare variants may contribute to BD susceptibility. To identify rare, high-penetrance susceptibility variants for BD, whole-exome sequencing (WES) was performed in three affected individuals from each of 27 multiply affected families from Spain and Germany. WES identified 378 rare, non-synonymous, and potentially functional variants. These spanned 368 genes, and were carried by all three affected members in at least one family. Eight of the 368 genes harbored rare variants that were implicated in at least two independent families. In an extended segregation analysis involving additional family members, five of these eight genes harbored variants showing full or nearly full cosegregation with BD. These included the brain-expressed genes RGS12 and NCKAP5, which were considered the most promising BD candidates on the basis of independent evidence. Gene enrichment analysis for all 368 genes revealed significant enrichment for four pathways, including genes reported in de novo studies of autism (padj padj = 0.015). These results suggest a possible genetic overlap with BD for autism and schizophrenia at the rare-sequence-variant level. The present study implicates novel candidate genes for BD development, and may contribute to an improved understanding of the biological basis of this common and often devastating disease.
Published: 2020

23. Who transitions to bipolar disorder? A comparison of major depressive disorder, anxiety, and ADHD.

Author: Li K, Rodriguez KM, Zandi P, and Goes FS
Abstract: Background: Diagnostic delays in Bipolar Disorder (BD) are common and may contribute to worse outcomes. While most studies focus on depression as a primary precursor, both anxiety and attention deficit disorders are also frequent initial diagnoses. In the current study, we utilized a large, diverse electronic health record (EHR) dataset to quantify the rates and correlates of conversion to BD from these major precursor diagnoses., Methods: Our study analyzed a comprehensive ten-year EHR dataset from Johns Hopkins Medicine, a diverse urban medical center, to assess and compare the rates and correlates of conversion to BD from Major Depressive Disorder (MDD), anxiety disorders, and ADHD. Risk factors for transition were assessed as time-varying variables in proportional hazards models., Results: Of the 21,341 patients initially included, 1232 later transitioned to a diagnosis of BD. Adjusted-one-year conversion rates for patients with MDD, anxiety disorders, and ADHD were 4.2 %, 3.4 %, and 4.0 %, respectively, with ten-year rates at 11.4 %, 9.4 %, and 10.9 %, respectively. Age (19-29 years), treatment setting (emergency and inpatient), and psychotropic medications were associated with conversion to BD across all precursor diagnoses. Severe and psychotic forms of MDD were among the strongest risk factors for transitioning to BD. Although risk factors for convertion were similar, transition rates were lower in children, particularly in indivudals with ADHD, who showed a higher rate of BD conversion in adults., Conclusions: The highest risk of transitioning to BD was observed in patients initially diagnosed with MDD, though significant risk was also noted in those with initial diagnoses of anxiety disorders and adult ADHD., Competing Interests: Declaration of competing interest All authors declare that they have no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)
Published: 2024
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24. Genetic signatures of AKT1 variants associated with worse COVID-19 outcomes - a multicentric observational study.

Author: de Almeida IM, Tosta BR, Pena LDC, Silva HDS, Reis-Goes FS, Silva NN, Cruz JVA, Silva MDA, de Araújo JF, Rodrigues JL, Oliveira G, Figueiredo RG, Vaz SN, Montaño-Castellón I, Santana D, Torres A, Beltrão FEL, Carneiro VL, Campos GS, Brites C, Fortuna V, Figueiredo CA, Trindade SC, Ramos HE, and Costa RDS
Subjects: Humans, Male, Middle Aged, Female, Aged, Adult, Polymorphism, Single Nucleotide, Fibrin Fibrinogen Degradation Products metabolism, Fibrin Fibrinogen Degradation Products analysis, Cytokines blood, Cytokines genetics, COVID-19 genetics, COVID-19 immunology, COVID-19 mortality, Proto-Oncogene Proteins c-akt genetics, SARS-CoV-2 physiology, Severity of Illness Index
Abstract: Introduction: The COVID-19, triggered by the SARS-CoV-2 virus, has varied clinical manifestations, ranging from mild cases to severe forms such as fatal pneumonia and acute respiratory distress syndrome (ARDS). Disease severity is influenced by an exacerbated immune response, characterized by high pro-inflammatory cytokine levels. Inhibition of AKT can potentially suppress pathological inflammation, cytokine storm and platelet activation associated with COVID-19. In this study, we aimed to investigate the rs2494746 and rs1130214 variants in the AKT1 gene associated with severe COVID-19 outcomes., Methods: Peripheral blood samples and sociodemographic data from 508 individuals with COVID-19, measuring plasma cytokine concentrations using ELISA and genotyped the AKT1 variants., Results: The rs2494746-C allele was associated with severity, ICU admission, and death from COVID-19. The C allele at rs1130214 was linked to increased TNF and D-dimer levels. Moreover, both variants exhibited an increased cumulative risk of disease severity, ICU admission, and mortality caused by COVID-19. In the predictive analysis, the rs2494746 obtained an accuracy of 71%, suggesting a high probability of the test determining the severity of the disease., Discussion: Our findings contribute to understanding the influence of the AKT1 gene variants on the immunological damage in individuals infected with SARS-CoV-2., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 de Almeida, Tosta, Pena, Silva, Reis-Goes, Silva, Cruz, Silva, de Araújo, Rodrigues, Oliveira, Figueiredo, Vaz, Montaño-Castellón, Santana, Torres, Beltrão, Carneiro, Campos, Brites, Fortuna, Figueiredo, Trindade, Ramos and Costa.)
Published: 2024
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25. Exploring the genetics of lithium response in bipolar disorders.

Author: Herrera-Rivero M, Adli M, Akiyama K, Akula N, Amare AT, Ardau R, Arias B, Aubry JM, Backlund L, Bellivier F, Benabarre A, Bengesser S, Bhattacharjee AK, Biernacka JM, Birner A, Cearns M, Cervantes P, Chen HC, Chillotti C, Cichon S, Clark SR, Colom F, Cruceanu C, Czerski PM, Dalkner N, Degenhardt F, Del Zompo M, DePaulo JR, Etain B, Falkai P, Ferensztajn-Rochowiak E, Forstner AJ, Frank J, Frisén L, Frye MA, Fullerton JM, Gallo C, Gard S, Garnham JS, Goes FS, Grigoroiu-Serbanescu M, Grof P, Hashimoto R, Hasler R, Hauser J, Heilbronner U, Herms S, Hoffmann P, Hou L, Hsu YH, Jamain S, Jiménez E, Kahn JP, Kassem L, Kato T, Kelsoe J, Kittel-Schneider S, Kuo PH, Kusumi I, König B, Laje G, Landén M, Lavebratt C, Leboyer M, Leckband SG, Maj M, Manchia M, Marie-Claire C, Martinsson L, McCarthy MJ, McElroy SL, Millischer V, Mitjans M, Mondimore FM, Monteleone P, Nievergelt CM, Novák T, Nöthen MM, O'Donovan C, Ozaki N, Papiol S, Pfennig A, Pisanu C, Potash JB, Reif A, Reininghaus E, Richard-Lepouriel H, Roberts G, Rouleau GA, Rybakowski JK, Schalling M, Schofield PR, Schubert KO, Schulte EC, Schweizer BW, Severino G, Shekhtman T, Shilling PD, Shimoda K, Simhandl C, Slaney CM, Squassina A, Stamm T, Stopkova P, Streit F, Tekola-Ayele F, Thalamuthu A, Tortorella A, Turecki G, Veeh J, Vieta E, Viswanath B, Witt SH, Zandi PP, Alda M, Bauer M, McMahon FJ, Mitchell PB, Rietschel M, Schulze TG, and Baune BT
Abstract: Background: Lithium (Li) remains the treatment of choice for bipolar disorders (BP). Its mood-stabilizing effects help reduce the long-term burden of mania, depression and suicide risk in patients with BP. It also has been shown to have beneficial effects on disease-associated conditions, including sleep and cardiovascular disorders. However, the individual responses to Li treatment vary within and between diagnostic subtypes of BP (e.g. BP-I and BP-II) according to the clinical presentation. Moreover, long-term Li treatment has been linked to adverse side-effects that are a cause of concern and non-adherence, including the risk of developing chronic medical conditions such as thyroid and renal disease. In recent years, studies by the Consortium on Lithium Genetics (ConLiGen) have uncovered a number of genetic factors that contribute to the variability in Li treatment response in patients with BP. Here, we leveraged the ConLiGen cohort (N = 2064) to investigate the genetic basis of Li effects in BP. For this, we studied how Li response and linked genes associate with the psychiatric symptoms and polygenic load for medical comorbidities, placing particular emphasis on identifying differences between BP-I and BP-II., Results: We found that clinical response to Li treatment, measured with the Alda scale, was associated with a diminished burden of mania, depression, substance and alcohol abuse, psychosis and suicidal ideation in patients with BP-I and, in patients with BP-II, of depression only. Our genetic analyses showed that a stronger clinical response to Li was modestly related to lower polygenic load for diabetes and hypertension in BP-I but not BP-II. Moreover, our results suggested that a number of genes that have been previously linked to Li response variability in BP differentially relate to the psychiatric symptomatology, particularly to the numbers of manic and depressive episodes, and to the polygenic load for comorbid conditions, including diabetes, hypertension and hypothyroidism., Conclusions: Taken together, our findings suggest that the effects of Li on symptomatology and comorbidity in BP are partially modulated by common genetic factors, with differential effects between BP-I and BP-II., (© 2024. The Author(s).)
Published: 2024
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26. Change in neurocognitive functioning in patients with treatment-resistant depression with serial intravenous ketamine infusions: The Bio-K multicenter trial.

Author: Singh B, Parikh SV, Voort JLV, Pazdernik VK, Achtyes ED, Goes FS, Yocum AK, Nykamp L, Becerra A, Smart L, Greden JF, Bobo WV, Frye MA, Burdick KE, and Ryan KA
Subjects: Adult, Humans, Depression, Infusions, Intravenous, Remission Induction, Depressive Disorder, Treatment-Resistant drug therapy, Depressive Disorder, Treatment-Resistant psychology, Ketamine pharmacology, Ketamine therapeutic use
Abstract: This nonrandomized, multicenter, open-label clinical trial explored the impact of intravenous (IV) ketamine on cognitive function in adults (n = 74) with treatment-resistant depression (TRD). Patients received three IV ketamine infusions during the acute phase and, if remitted, four additional infusions in the continuation phase (Mayo site). Cognitive assessments using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) were conducted at baseline, end of the acute phase, and end of the continuation phase (Mayo site). Results showed a significant 53 % (39/74) remission rate in depression symptoms after the acute phase. In adjusted models, baseline language domain score was associated with a higher odd of remission (Odds Ratio, 1.09, 95 % CI = 1.03-1.17, p = 0.004) and greater improvement in MADRS at the end of the acute phase (β =-0.97; 95 % CI, -1.74 to -0.20; P = 0.02). The likelihood of remission was not significantly associated with baseline immediate or delayed memory, visuospatial/constructional, or attention scores. In the continuation phase, improvements in immediate and delayed memory and attention persisted, with additional gains in visuospatial and language domains. Limitations included an open-label design, potential practice effects, and ongoing psychotropic medication use. Overall, the study suggests cognitive improvement, not deterioration, associated with serial IV ketamine administrations for TRD. These findings encourage future studies with larger sample sizes and longer follow-up periods to examine any potential for deleterious effect with recurrent ketamine use for TRD. Trial Registration: ClinicalTrials.gov: NCT03156504., Competing Interests: Declaration of competing interest BS received research grant support from Mayo Clinic, National Network of Depression Centers (NNDC), and BD2 (Breakthrough Discoveries for thriving with Bipolar Disorder). SVP has received honoraria for consulting or research funds from the Canadian Institutes for Health Research, Ontario Brain Institute, and Aifred, Janssen, Merck, Mensante, Neonmind, Otsuka, Sage, and Takeda. JLVV has received a grant-in-kind for supplies and genotyping from Assurex Health. EDA has received research support from the following entities in the preceding 12 months: Alkermes, Boehringer-Ingelheim, Janssen, Karuna, Neurocrine Biosciences, Takeda, Teva, and the Vanguard Research Group. EDA also has served on advisory boards or consulted with Alkermes, Clinical Care Options, CMEology, CME Outfitters, Indivior, Karuna, and Teva. FSG has received research grant support from Janssen Therapeutics. WVB has received grant funding or research support from the NIH, AHRQ, National Science Foundation, the Watzinger Foundation, the Myocarditis Foundation, the Blue Gator Foundation, and the Mayo Foundation for Medical Education and Research. MAF has received Grant Support from Assurex Health, Breakthrough Discoveries for Thriving with Bipolar Disorder (BD2), and Mayo Foundation. CME/Travel/Honoraria or Consultant Carnot Laboratories, American Physician Institute. He also has financial interests in Chymia LLC. KEB has received grants from Janssen Pharmaceuticals and has received honorarium as an advisory board member for The Bipolar Roadmap Initiative (Milken Institute for Strategic Philanthropy) and Breakthrough Discoveries for thriving with Bipolar Disorder (BD2). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)
Published: 2024
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27. Genome-wide association study identifies 30 obsessive-compulsive disorder associated loci.

Author: Strom NI, Gerring ZF, Galimberti M, Yu D, Halvorsen MW, Abdellaoui A, Rodriguez-Fontenla C, Sealock JM, Bigdeli T, Coleman JR, Mahjani B, Thorp JG, Bey K, Burton CL, Luykx JJ, Zai G, Alemany S, Andre C, Askland KD, Banaj N, Barlassina C, Nissen JB, Bienvenu OJ, Black D, Bloch MH, Boberg J, Børte S, Bosch R, Breen M, Brennan BP, Brentani H, Buxbaum JD, Bybjerg-Grauholm J, Byrne EM, Cabana-Dominguez J, Camarena B, Camarena A, Cappi C, Carracedo A, Casas M, Cavallini MC, Ciullo V, Cook EH, Crosby J, Cullen BA, De Schipper EJ, Delorme R, Djurovic S, Elias JA, Estivill X, Falkenstein MJ, Fundin BT, Garner L, German C, Gironda C, Goes FS, Grados MA, Grove J, Guo W, Haavik J, Hagen K, Harrington K, Havdahl A, Höffler KD, Hounie AG, Hucks D, Hultman C, Janecka M, Jenike E, Karlsson EK, Kelley K, Klawohn J, Krasnow JE, Krebs K, Lange C, Lanzagorta N, Levey D, Lindblad-Toh K, Macciardi F, Maher B, Mathes B, McArthur E, McGregor N, McLaughlin NC, Meier S, Miguel EC, Mulhern M, Nestadt PS, Nurmi EL, O'Connell KS, Osiecki L, Ousdal OT, Palviainen T, Pedersen NL, Piras F, Piras F, Potluri S, Rabionet R, Ramirez A, Rauch S, Reichenberg A, Riddle MA, Ripke S, Rosário MC, Sampaio AS, Schiele MA, Skogholt AH, Sloofman LGSG, Smit J, Soler AM, Thomas LF, Tifft E, Vallada H, van Kirk N, Veenstra-VanderWeele J, Vulink NN, Walker CP, Wang Y, Wendland JR, Winsvold BS, Yao Y, Zhou H, Agrawal A, Alonso P, Berberich G, Bucholz KK, Bulik CM, Cath D, Denys D, Eapen V, Edenberg H, Falkai P, Fernandez TV, Fyer AJ, Gaziano JM, Geller DA, Grabe HJ, Greenberg BD, Hanna GL, Hickie IB, Hougaard DM, Kathmann N, Kennedy J, Lai D, Landén M, Le Hellard S, Leboyer M, Lochner C, McCracken JT, Medland SE, Mortensen PB, Neale BM, Nicolini H, Nordentoft M, Pato M, Pato C, Pauls DL, Piacentini J, Pittenger C, Posthuma D, Ramos-Quiroga JA, Rasmussen SA, Richter MA, Rosenberg DR, Ruhrmann S, Samuels JF, Sandin S, Sandor P, Spalletta G, Stein DJ, Stewart SE, Storch EA, Stranger BE, Turiel M, Werge T, Andreassen OA, Børglum AD, Walitza S, Hveem K, Hansen BK, Rück CP, Martin NG, Milani L, Mors O, Reichborn-Kjennerud T, Ribasés M, Kvale G, Mataix-Cols D, Domschke K, Grünblatt E, Wagner M, Zwart JA, Breen G, Nestadt G, Kaprio J, Arnold PD, Grice DE, Knowles JA, Ask H, Verweij KJ, Davis LK, Smit DJ, Crowley JJ, Scharf JM, Stein MB, Gelernter J, Mathews CA, Derks EM, and Mattheisen M
Abstract: Obsessive-compulsive disorder (OCD) affects ~1% of the population and exhibits a high SNP-heritability, yet previous genome-wide association studies (GWAS) have provided limited information on the genetic etiology and underlying biological mechanisms of the disorder. We conducted a GWAS meta-analysis combining 53,660 OCD cases and 2,044,417 controls from 28 European-ancestry cohorts revealing 30 independent genome-wide significant SNPs and a SNP-based heritability of 6.7%. Separate GWAS for clinical, biobank, comorbid, and self-report sub-groups found no evidence of sample ascertainment impacting our results. Functional and positional QTL gene-based approaches identified 249 significant candidate risk genes for OCD, of which 25 were identified as putatively causal, highlighting WDR6 , DALRD3 , CTNND1 and genes in the MHC region. Tissue and single-cell enrichment analyses highlighted hippocampal and cortical excitatory neurons, along with D1- and D2-type dopamine receptor-containing medium spiny neurons, as playing a role in OCD risk. OCD displayed significant genetic correlations with 65 out of 112 examined phenotypes. Notably, it showed positive genetic correlations with all included psychiatric phenotypes, in particular anxiety, depression, anorexia nervosa, and Tourette syndrome, and negative correlations with a subset of the included autoimmune disorders, educational attainment, and body mass index.. This study marks a significant step toward unraveling its genetic landscape and advances understanding of OCD genetics, providing a foundation for future interventions to address this debilitating disorder., Competing Interests: Chris German is employed by and hold stock or stock options in 23andMe, Inc. Erika L. Nurmi is on the Scientific Advisory Board for Myriad Genetics and Medical Advisory Board for Tourette Association of America and received Clinical trial funding from Emalex and Octapharma Pharmaceuticals. Jeremy Veenstra-VanderWeele has served on advisory boards or consulted with Roche, Novartis, and SynapDx; received research funding from Roche, Novartis, SynapDx, Seaside Therapeutics, Forest, Janssen, Acadia, Yamo, and MapLight; received stipends for editorial work from Wiley and Springer. Jens R. Wendland is a current employee and shareholder of Takeda Pharmaceuticals and a past employee and shareholder of F. Hoffmann-La Roche, Pfizer and Nestle Health Science. Cynthia M. Bulik reports: Pearson (author, royalty recipient).Peter Falkai reports no conflict of interest regarding this study and reports to have received financial support and Advisory Board: Richter, Recordati, Boehringer-Ingelheim, Otsuka, Janssen and Lundbeck. Hans J. Grabe has received travel grants and speakers honoraria from Fresenius Medical Care, Neuraxpharm, Servier and Janssen Cilag as well as research funding from Fresenius Medical Care. Ian B. Hickie is the Co-Director, Health and Policy at the Brain and Mind Centre (BMC) University of Sydney, Australia. The BMC operates an early-intervention youth services at Camperdown under contract to headspace. Professor Hickie has previously led community-based and pharmaceutical industry-supported (Wyeth, Eli Lily, Servier, Pfizer, AstraZeneca, Janssen Cilag) projects focused on the identification and better management of anxiety and depression. He is the Chief Scientific Advisor to, and a 3.2% equity shareholder in, InnoWell Pty Ltd which aims to transform mental health services through the use of innovative technologies. Benjamin M. Neale is a member of the scientific advisory board at Deep Genomics and Neumora. Christopher Pittenger consults and/or receives research support from Biohaven Pharmaceuticals, Freedom Biosciences, Ceruvia Lifesciences, Transcend Therapeutics, UCB BioPharma, and F-Prime Capital Partners. He owns equity in Alco Therapeutics. These relationships are not related to the current work. Dan J. Stein has received consultancy honoraria from Discovery Vitality, Johnson & Johnson, Kanna, L’Oreal, Lundbeck, Orion, Sanofi, Servier, Takeda and Vistagen. Eric A. Storch reports receiving research funding to his institution from the Ream Foundation, International OCD Foundation, and NIH. He was formerly a consultant for Brainsway and Biohaven Pharmaceuticals in the past 12 months. He owns stock less than $5000 in NView/Proem for distribution related to the YBOCS scales. He receives book royalties from Elsevier, Wiley, Oxford, American Psychological Association, Guildford, Springer, Routledge, and Jessica Kingsley. Ole A. Andreasson reports to be a consultant to Cortechs.ai, Precision Health AS, speakers honorarium from Otsuka, Lundbeck, Sunovion, Janssen. Anders D. Børglum has received speaker fee from Lundbeck. David Mataix-Cols receives royalties for contributing articles to UpToDate, Wolters Kluwer Health, and personal fees for editorial work from Elsevier, all unrelated to the current work. Murray B. Stein has in the past 3 years received consulting income from Acadia Pharmaceuticals, BigHealth, Biogen, Bionomics, Boehringer Ingelheim, Clexio, Eisai, EmpowerPharm, Engrail Therapeutics, Janssen, Jazz Pharmaceuticals, NeuroTrauma Sciences, Otsuka, PureTech Health, Sage Therapeutics, Sumitomo Pharma, and Roche/Genentech. Dr. Stein has stock options in Oxeia Biopharmaceuticals and EpiVario. He has been paid for his editorial work on Depression and Anxiety (Editor-in-Chief), Biological Psychiatry (Deputy Editor), and UpToDate (Co-Editor-in-Chief for Psychiatry). Joel Gelernter is paid for editorial work by the journal Complex Psychiatry. Pino Alonso has received funding from Biohaven, Boston Scientific, Medtronic. All other authors report no conflicts of interest.
Published: 2024
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28. Clinical outcomes in the biomarkers of ketamine (Bio-K) study of open-label IV ketamine for refractory depression.

Author: Parikh SV, Vande Voort JL, Yocum AK, Achtyes E, Goes FS, Nykamp L, Singh B, Lopez-Vives D, Sera CE, Maixner D, Tarnal V, Severe J, Bartek S, Tye SJ, Rico J, Stoppel CJ, Becerra A, Smart L, Miller CR, Frye MA, Greden JF, and Bobo WV
Subjects: Humans, Treatment Outcome, Infusions, Intravenous, Biomarkers, Depression, Ketamine adverse effects, Depressive Disorder, Major drug therapy, Depressive Disorder, Treatment-Resistant drug therapy, Depressive Disorder, Treatment-Resistant diagnosis, Bipolar Disorder drug therapy
Abstract: Objective: We conducted an open-label clinical trial ("Bio-K") using IV ketamine for treatment-resistant depression to identify biomarkers linked to remission. Here, we report the clinical efficacy and side effect outcomes of Bio-K., Methods: Across 4 US sites, 75 patients ages 18-65 with treatment-refractory unipolar or bipolar depression received 3 IV ketamine infusions over an 11-day period. Key exclusion criteria were psychotic symptoms, significant substance abuse, unstable medical conditions, and any use of cannabis. Pre-existing antidepressant medication was maintained. Primary outcome was remission as measured by Montgomery-Asberg Depression Rating Scale (MADRS), with secondary outcome of 50 % reduction in Beck Suicide Scale score. Safety monitoring and varying durations of infusions were also key parameters., Results: Using remission as MADRS score <10, after 3 infusions 52 % achieved remission, with 67 % achieving response. Of those achieving response after a single infusion, 66 % (22 of 33) reached remission after 3 infusions, while 40 % (16 of 40) non-responders after the first infusion went on to achieve remission after 3 infusions. Only 20 % of non-responders after 2 infusions achieved remission. Most (81 %) participants had significant suicidal ideation at baseline; of these, two-thirds (67 %) experienced at least a 50 % reduction in suicidality. Side effects were minimal. Uniquely, we had three different types of infusion categories, with individuals receiving: (1) slow (100-min) infusions only or (2) regular (40-min) infusions only or (3) a mix of infusion durations. These three infusion groups showed comparable safety and efficacy. Exploration of clinical factors revealed no link between BMI, age, or gender to remission., Conclusions: The consistency of outcomes across 4 clinical sites and across multiple instruments, suggests high acute efficacy and safety of IV ketamine for serious depressive episodes. Duration of infusion did not alter outcomes. Meaningfully, 40 % of non-responders after a single infusion did reach remission subsequently, while only 20 % of non-responders after 2 infusions achieved remission, suggesting early response is suggestive for eventual remission. Our data on varying ketamine infusion duration adds novel insights into the clinical administration of this new treatment for refractory and severe patients. Our limitations included a lack of a control group, necessitating caution about conclusions of efficacy, balanced by the utility of reporting "real-world" outcomes across multiple clinical sites. We could also not separately analyze results for bipolar disorder due to small numbers. Together, the Bio-K clinical results are promising and provide significant sample sizes for forthcoming biological markers analyses., Competing Interests: Declaration of competing interest Anastasia Yocum, Alexis Becerra, William Bobo, Jennifer Severe, Steven Bartek, Daniel Maixner, Christina Miller, Louis Nykamp, Daniela Lopez-Vives, Cortney E. Sera, LeAnn Smart, Susannah Tye, Jose Rico, Cynthia Stoppel, and John Greden have no conflicts of interest to declare. Dr. Parikh has received honoraria for consulting or research funds from the Canadian Institutes for Health Research, Ontario Brain Institute, and Aifred, Janssen, Merck, Mensante, Neonmind, Otsuka, Sage, and Takeda. Dr. Vande Voort has received grant-in-kind support for supplies and genotyping from Assurex Health. Dr. Achtyes has served on advisory boards or consulted for Alkermes, Atheneum, Janssen, Karuna, Lundbeck/Otsuka, Roche, Sunovion and Teva and reports previous stock holdings in AstraZeneca, Johnson & Johnson, Moderna, and Pfizer. Dr. Achtyes has received research support from Alkermes, Astellas, Biogen, Boehringer-Ingelheim, InnateVR, Janssen, National Network of Depression Centers, Neurocrine Biosciences, Novartis, Otsuka, Pear Therapeutics, and Takeda. Dr. Achtyes serves as an advisor to CAPNOS Zero, the World Psychiatric Association and Clubhouse International, and the SMI Adviser LAI Center of Excellence (all unpaid). Dr. Goes has received research grant support from Janssen Therapeutics. Dr. Tarnal has received research support from TRYP Therapeutics. Dr. Frye has received Grant Support from Assurex Health, and Mayo Foundation. He also has financial interests in Chymia LLC. Dr. Singh has received research support from the Mayo Clinic., (Copyright © 2023. Published by Elsevier B.V.)
Published: 2024
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29. Lithium response in bipolar disorder is associated with focal adhesion and PI3K-Akt networks: a multi-omics replication study.

Author: Ou AH, Rosenthal SB, Adli M, Akiyama K, Akula N, Alda M, Amare AT, Ardau R, Arias B, Aubry JM, Backlund L, Bauer M, Baune BT, Bellivier F, Benabarre A, Bengesser S, Bhattacharjee AK, Biernacka JM, Cervantes P, Chen GB, Chen HC, Chillotti C, Cichon S, Clark SR, Colom F, Cousins DA, Cruceanu C, Czerski PM, Dantas CR, Dayer A, Del Zompo M, Degenhardt F, DePaulo JR, Étain B, Falkai P, Fellendorf FT, Ferensztajn-Rochowiak E, Forstner AJ, Frisén L, Frye MA, Fullerton JM, Gard S, Garnham JS, Goes FS, Grigoroiu-Serbanescu M, Grof P, Gruber O, Hashimoto R, Hauser J, Heilbronner U, Herms S, Hoffmann P, Hofmann A, Hou L, Jamain S, Jiménez E, Kahn JP, Kassem L, Kato T, Kittel-Schneider S, König B, Kuo PH, Kusumi I, Lackner N, Laje G, Landén M, Lavebratt C, Leboyer M, Leckband SG, Jaramillo CAL, MacQueen G, Maj M, Manchia M, Marie-Claire C, Martinsson L, Mattheisen M, McCarthy MJ, McElroy SL, McMahon FJ, Mitchell PB, Mitjans M, Mondimore FM, Monteleone P, Nievergelt CM, Nöthen MM, Novák T, Ösby U, Ozaki N, Papiol S, Perlis RH, Pisanu C, Potash JB, Pfennig A, Reich-Erkelenz D, Reif A, Reininghaus EZ, Rietschel M, Rouleau GA, Rybakowski JK, Schalling M, Schofield PR, Schubert KO, Schulze TG, Schweizer BW, Seemüller F, Severino G, Shekhtman T, Shilling PD, Shimoda K, Simhandl C, Slaney CM, Squassina A, Stamm T, Stopkova P, Tighe SK, Tortorella A, Turecki G, Vieta E, Volkert J, Witt S, Wray NR, Wright A, Young LT, Zandi PP, and Kelsoe JR
Subjects: Humans, Proto-Oncogene Proteins c-akt genetics, Phosphatidylinositol 3-Kinases genetics, Genome-Wide Association Study, Multiomics, Focal Adhesions, Lithium pharmacology, Lithium therapeutic use, Bipolar Disorder drug therapy, Bipolar Disorder genetics
Abstract: Lithium is the gold standard treatment for bipolar disorder (BD). However, its mechanism of action is incompletely understood, and prediction of treatment outcomes is limited. In our previous multi-omics study of the Pharmacogenomics of Bipolar Disorder (PGBD) sample combining transcriptomic and genomic data, we found that focal adhesion, the extracellular matrix (ECM), and PI3K-Akt signaling networks were associated with response to lithium. In this study, we replicated the results of our previous study using network propagation methods in a genome-wide association study of an independent sample of 2039 patients from the International Consortium on Lithium Genetics (ConLiGen) study. We identified functional enrichment in focal adhesion and PI3K-Akt pathways, but we did not find an association with the ECM pathway. Our results suggest that deficits in the neuronal growth cone and PI3K-Akt signaling, but not in ECM proteins, may influence response to lithium in BD., (© 2024. The Author(s).)
Published: 2024
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30. Trends in Telepsychiatry and In-Person Psychiatric Care for Depression in an Academic Health System, 2017-2022.

Author: Ettman CK, Brantner CL, Albert M, Goes FS, Mojtabai R, Spivak S, Stuart EA, and Zandi PP
Subjects: Humans, Pandemics, Depression, Ambulatory Care, Telemedicine, Psychiatry
Abstract: Objective: The authors aimed to assess differences in appointment completion rates between telepsychiatry and in-person outpatient psychiatric care for patients with depression in an academic health system., Methods: Electronic health records of encounters for patients (ages ≥10) with a depression diagnosis and at least one scheduled outpatient psychiatric appointment (N=586,266 appointments; November 2017-October 2022) were assessed for appointment volume and completion of telepsychiatry versus in-person sessions., Results: Telepsychiatry became the dominant care modality after the onset of the COVID-19 pandemic, although the number of telepsychiatry and in-person appointments nearly converged by October 2022. Logistic regression showed that telepsychiatry appointments (July 2020-October 2022) were more likely (OR=1.30, 95% CI=1.27-1.34) to be completed than in-person appointments., Conclusions: Telepsychiatry appointments were less likely to be canceled or missed than in-person appointments, suggesting that telepsychiatry improved efficiency and continuity of care. As in-person operations resume following the pandemic, maintaining telepsychiatry services may optimize hospital-level and patient outcomes., Competing Interests: Dr. Mojtabai reports having received royalties from UpToDate and Medscape and providing expert consultation regarding social media litigation on behalf of the plaintiffs. The other authors report no financial relationships with commercial interests.
Published: 2024
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31. Identifying genetic differences between bipolar disorder and major depression through multiple GWAS.

Author: Panagiotaropoulou G, Hellberg KG, Coleman JRI, Seok D, Kalman J, Mitchell PB, Schofield PR, Forstner AJ, Bauer M, Scott LJ, Pato CN, Pato MT, Li QS, Kirov G, Landén M, Jonsson L, Müller-Myhsok B, Smoller JW, Binder EB, Brückl TM, Czamara D, der Auwera SV, Grabe HJ, Homuth G, Schmidt CO, Potash JB, DePaulo RJ, Goes FS, MacKinnon DF, Mondimore FM, Weissman MM, Shi J, Frye MA, Biernacka JM, Reif A, Witt SH, Kahn RR, Boks MM, Owen MJ, Gordon-Smith K, Mitchell BL, Martin NG, Medland SE, Jones L, Knowles JA, Levinson DF, O'Donovan MC, Lewis CM, Breen G, Werge T, Schork AJ, Ophoff R, Ripke S, and Loohuis LO
Abstract: Background: Accurate diagnosis of bipolar disorder (BD) is difficult in clinical practice, with an average delay between symptom onset and diagnosis of about 7 years. A key reason is that the first manic episode is often preceded by a depressive one, making it difficult to distinguish BD from unipolar major depressive disorder (MDD)., Aims: Here, we use genome-wide association analyses (GWAS) to identify differential genetic factors and to develop predictors based on polygenic risk scores that may aid early differential diagnosis., Methods: Based on individual genotypes from case-control cohorts of BD and MDD shared through the Psychiatric Genomics Consortium, we compile case-case-control cohorts, applying a careful merging and quality control procedure. In a resulting cohort of 51,149 individuals (15,532 BD cases, 12,920 MDD cases and 22,697 controls), we perform a variety of GWAS and polygenic risk scores (PRS) analyses., Results: While our GWAS is not well-powered to identify genome-wide significant loci, we find significant SNP-heritability and demonstrate the ability of the resulting PRS to distinguish BD from MDD, including BD cases with depressive onset. We replicate our PRS findings, but not signals of individual loci in an independent Danish cohort (iPSYCH 2015 case-cohort study, N=25,966). We observe strong genetic correlation between our case-case GWAS and that of case-control BD., Conclusions: We find that MDD and BD, including BD with a depressive onset, are genetically distinct. Further, our findings support the hypothesis that Controls - MDD - BD primarily lie on a continuum of genetic risk. Future studies with larger and richer samples will likely yield a better understanding of these findings and enable the development of better genetic predictors distinguishing BD and, importantly, BD with depressive onset from MDD.
Published: 2024
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32. The Human Phenotype Ontology in 2024: phenotypes around the world.

Author: Gargano MA, Matentzoglu N, Coleman B, Addo-Lartey EB, Anagnostopoulos AV, Anderton J, Avillach P, Bagley AM, Bakštein E, Balhoff JP, Baynam G, Bello SM, Berk M, Bertram H, Bishop S, Blau H, Bodenstein DF, Botas P, Boztug K, Čady J, Callahan TJ, Cameron R, Carbon SJ, Castellanos F, Caufield JH, Chan LE, Chute CG, Cruz-Rojo J, Dahan-Oliel N, Davids JR, de Dieuleveult M, de Souza V, de Vries BBA, de Vries E, DePaulo JR, Derfalvi B, Dhombres F, Diaz-Byrd C, Dingemans AJM, Donadille B, Duyzend M, Elfeky R, Essaid S, Fabrizzi C, Fico G, Firth HV, Freudenberg-Hua Y, Fullerton JM, Gabriel DL, Gilmour K, Giordano J, Goes FS, Moses RG, Green I, Griese M, Groza T, Gu W, Guthrie J, Gyori B, Hamosh A, Hanauer M, Hanušová K, He YO, Hegde H, Helbig I, Holasová K, Hoyt CT, Huang S, Hurwitz E, Jacobsen JOB, Jiang X, Joseph L, Keramatian K, King B, Knoflach K, Koolen DA, Kraus ML, Kroll C, Kusters M, Ladewig MS, Lagorce D, Lai MC, Lapunzina P, Laraway B, Lewis-Smith D, Li X, Lucano C, Majd M, Marazita ML, Martinez-Glez V, McHenry TH, McInnis MG, McMurry JA, Mihulová M, Millett CE, Mitchell PB, Moslerová V, Narutomi K, Nematollahi S, Nevado J, Nierenberg AA, Čajbiková NN, Nurnberger JI Jr, Ogishima S, Olson D, Ortiz A, Pachajoa H, Perez de Nanclares G, Peters A, Putman T, Rapp CK, Rath A, Reese J, Rekerle L, Roberts AM, Roy S, Sanders SJ, Schuetz C, Schulte EC, Schulze TG, Schwarz M, Scott K, Seelow D, Seitz B, Shen Y, Similuk MN, Simon ES, Singh B, Smedley D, Smith CL, Smolinsky JT, Sperry S, Stafford E, Stefancsik R, Steinhaus R, Strawbridge R, Sundaramurthi JC, Talapova P, Tenorio Castano JA, Tesner P, Thomas RH, Thurm A, Turnovec M, van Gijn ME, Vasilevsky NA, Vlčková M, Walden A, Wang K, Wapner R, Ware JS, Wiafe AA, Wiafe SA, Wiggins LD, Williams AE, Wu C, Wyrwoll MJ, Xiong H, Yalin N, Yamamoto Y, Yatham LN, Yocum AK, Young AH, Yüksel Z, Zandi PP, Zankl A, Zarante I, Zvolský M, Toro S, Carmody LC, Harris NL, Munoz-Torres MC, Danis D, Mungall CJ, Köhler S, Haendel MA, and Robinson PN
Subjects: Humans, Phenotype, Genomics, Algorithms, Rare Diseases, Biological Ontologies
Abstract: The Human Phenotype Ontology (HPO) is a widely used resource that comprehensively organizes and defines the phenotypic features of human disease, enabling computational inference and supporting genomic and phenotypic analyses through semantic similarity and machine learning algorithms. The HPO has widespread applications in clinical diagnostics and translational research, including genomic diagnostics, gene-disease discovery, and cohort analytics. In recent years, groups around the world have developed translations of the HPO from English to other languages, and the HPO browser has been internationalized, allowing users to view HPO term labels and in many cases synonyms and definitions in ten languages in addition to English. Since our last report, a total of 2239 new HPO terms and 49235 new HPO annotations were developed, many in collaboration with external groups in the fields of psychiatry, arthrogryposis, immunology and cardiology. The Medical Action Ontology (MAxO) is a new effort to model treatments and other measures taken for clinical management. Finally, the HPO consortium is contributing to efforts to integrate the HPO and the GA4GH Phenopacket Schema into electronic health records (EHRs) with the goal of more standardized and computable integration of rare disease data in EHRs., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)
Published: 2024
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33. Characterizing the longitudinal course of symptoms and functioning in bipolar disorder.

Author: Mignogna KM and Goes FS
Subjects: Humans, Psychiatric Status Rating Scales, Comorbidity, Prognosis, Anxiety Disorders, Bipolar Disorder psychology
Abstract: Background: The course of Bipolar Disorder (BD) is highly variable, with marked inter and intra-individual differences in symptoms and functioning. In this study, we identified illness trajectories across major clinical domains that could have etiological, prognostic, and therapeutic relevance., Methods: Using the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study, we performed univariate and multivariate trajectory modeling of depressive symptoms, manic symptoms, and psychosocial functioning. Multinomial regression was performed to identify baseline variables associated with poor outcome trajectories., Results: Depressive symptoms predominated, with most subjects being found in trajectories characterized by various degrees of depressive symptoms and 13% of subjects being classified in a poor outcome 'persistently depressed' trajectory. Most subjects experienced few manic symptoms, although approximately 10% of subjects followed a trajectory of persistently manic symptoms. Trajectory analysis of psychosocial functioning showed impairment in most of the sample, with little improvement during follow up. Multi-trajectory analyses highlighted significant impairment in subjects with persistently mixed and persistently depressed trajectories of illness. In general, poor outcome trajectories were marked by lower educational attainment, higher unemployment and disability, and a greater likelihood of adverse clinical features (rapid cycling and suicide attempts) and comorbid diagnoses (anxiety disorders, PTSD, and substance abuse/dependence disorders)., Conclusions: Subjects with BD can be classified into several trajectories of clinically relevant domains that are prognostically relevant and show differing degrees of associations with a broad range of negative clinical risk factors. The highest level of psychosocial disability was found in subjects with chronic mixed and depressive symptoms, who show limited improvement despite guideline-based treatment.
Published: 2024
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34. Focal adhesion is associated with lithium response in bipolar disorder: evidence from a network-based multi-omics analysis.

Author: Niemsiri V, Rosenthal SB, Nievergelt CM, Maihofer AX, Marchetto MC, Santos R, Shekhtman T, Alliey-Rodriguez N, Anand A, Balaraman Y, Berrettini WH, Bertram H, Burdick KE, Calabrese JR, Calkin CV, Conroy C, Coryell WH, DeModena A, Eyler LT, Feeder S, Fisher C, Frazier N, Frye MA, Gao K, Garnham J, Gershon ES, Goes FS, Goto T, Harrington GJ, Jakobsen P, Kamali M, Kelly M, Leckband SG, Lohoff FW, McCarthy MJ, McInnis MG, Craig D, Millett CE, Mondimore F, Morken G, Nurnberger JI, Donovan CO, Øedegaard KJ, Ryan K, Schinagle M, Shilling PD, Slaney C, Stapp EK, Stautland A, Tarwater B, Zandi PP, Alda M, Fisch KM, Gage FH, and Kelsoe JR
Subjects: Humans, Neurons metabolism, Neurons drug effects, Induced Pluripotent Stem Cells drug effects, Induced Pluripotent Stem Cells metabolism, Pharmacogenetics methods, Antimanic Agents pharmacology, Antimanic Agents therapeutic use, Male, Female, Lithium Compounds pharmacology, Lithium Compounds therapeutic use, Gene Expression Profiling methods, Genomics methods, Multiomics, Bipolar Disorder drug therapy, Bipolar Disorder genetics, Lithium pharmacology, Lithium therapeutic use, Gene Regulatory Networks drug effects, Gene Regulatory Networks genetics, Focal Adhesions drug effects, Focal Adhesions genetics, Transcriptome genetics, Transcriptome drug effects, Genome-Wide Association Study methods
Abstract: Lithium (Li) is one of the most effective drugs for treating bipolar disorder (BD), however, there is presently no way to predict response to guide treatment. The aim of this study is to identify functional genes and pathways that distinguish BD Li responders (LR) from BD Li non-responders (NR). An initial Pharmacogenomics of Bipolar Disorder study (PGBD) GWAS of lithium response did not provide any significant results. As a result, we then employed network-based integrative analysis of transcriptomic and genomic data. In transcriptomic study of iPSC-derived neurons, 41 significantly differentially expressed (DE) genes were identified in LR vs NR regardless of lithium exposure. In the PGBD, post-GWAS gene prioritization using the GWA-boosting (GWAB) approach identified 1119 candidate genes. Following DE-derived network propagation, there was a highly significant overlap of genes between the top 500- and top 2000-proximal gene networks and the GWAB gene list (P hypergeometric = 1.28E-09 and 4.10E-18, respectively). Functional enrichment analyses of the top 500 proximal network genes identified focal adhesion and the extracellular matrix (ECM) as the most significant functions. Our findings suggest that the difference between LR and NR was a much greater effect than that of lithium. The direct impact of dysregulation of focal adhesion on axon guidance and neuronal circuits could underpin mechanisms of response to lithium, as well as underlying BD. It also highlights the power of integrative multi-omics analysis of transcriptomic and genomic profiling to gain molecular insights into lithium response in BD., (© 2023. The Author(s).)
Published: 2024
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35. Digital Phenotyping for Mood Disorders: Methodology-Oriented Pilot Feasibility Study.

Author: Breitinger S, Gardea-Resendez M, Langholm C, Xiong A, Laivell J, Stoppel C, Harper L, Volety R, Walker A, D'Mello R, Byun AJS, Zandi P, Goes FS, Frye M, and Torous J
Subjects: Humans, Female, Adult, Male, Feasibility Studies, Pilot Projects, Longitudinal Studies, Mood Disorders diagnosis, Bipolar Disorder diagnosis
Abstract: Background: In the burgeoning area of clinical digital phenotyping research, there is a dearth of literature that details methodology, including the key challenges and dilemmas in developing and implementing a successful architecture for technological infrastructure, patient engagement, longitudinal study participation, and successful reporting and analysis of diverse passive and active digital data streams., Objective: This article provides a narrative rationale for our study design in the context of the current evidence base and best practices, with an emphasis on our initial lessons learned from the implementation challenges and successes of this digital phenotyping study., Methods: We describe the design and implementation approach for a digital phenotyping pilot feasibility study with attention to synthesizing key literature and the reasoning for pragmatic adaptations in implementing a multisite study encompassing distinct geographic and population settings. This methodology was used to recruit patients as study participants with a clinician-validated diagnostic history of unipolar depression, bipolar I disorder, or bipolar II disorder, or healthy controls in 2 geographically distinct health care systems for a longitudinal digital phenotyping study of mood disorders., Results: We describe the feasibility of a multisite digital phenotyping pilot study for patients with mood disorders in terms of passively and actively collected phenotyping data quality and enrollment of patients. Overall data quality (assessed as the amount of sensor data obtained vs expected) was high compared to that in related studies. Results were reported on the relevant demographic features of study participants, revealing recruitment properties of age (mean subgroup age ranged from 31 years in the healthy control subgroup to 38 years in the bipolar I disorder subgroup), sex (predominance of female participants, with 7/11, 64% females in the bipolar II disorder subgroup), and smartphone operating system (iOS vs Android; iOS ranged from 7/11, 64% in the bipolar II disorder subgroup to 29/32, 91% in the healthy control subgroup). We also described implementation considerations around digital phenotyping research for mood disorders and other psychiatric conditions., Conclusions: Digital phenotyping in affective disorders is feasible on both Android and iOS smartphones, and the resulting data quality using an open-source platform is higher than that in comparable studies. While the digital phenotyping data quality was independent of gender and race, the reported demographic features of study participants revealed important information on possible selection biases that may result from naturalistic research in this domain. We believe that the methodology described will be readily reproducible and generalizable to other study settings and patient populations given our data on deployment at 2 unique sites., (©Scott Breitinger, Manuel Gardea-Resendez, Carsten Langholm, Ashley Xiong, Joseph Laivell, Cynthia Stoppel, Laura Harper, Rama Volety, Alex Walker, Ryan D'Mello, Andrew Jin Soo Byun, Peter Zandi, Fernando S Goes, Mark Frye, John Torous. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 29.12.2023.)
Published: 2023
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36. Exploring the genetics of lithium response in bipolar disorders.

Author: Herrera-Rivero M, Adli M, Akiyama K, Akula N, Amare AT, Ardau R, Arias B, Aubry JM, Backlund L, Bellivier F, Benabarre A, Bengesser S, Bhattacharjee AK, Biernacka JM, Birner A, Cearns M, Cervantes P, Chen HC, Chillotti C, Cichon S, Clark SR, Colom F, Cruceanu C, Czerski PM, Dalkner N, Degenhardt F, Del Zompo M, DePaulo JR, Etain B, Falkai P, Ferensztajn-Rochowiak E, Forstner AJ, Frank J, Frisén L, Frye MA, Fullerton JM, Gallo C, Gard S, Garnham JS, Goes FS, Grigoroiu-Serbanescu M, Grof P, Hashimoto R, Hasler R, Hauser J, Heilbronner U, Herms S, Hoffmann P, Hou L, Hsu YH, Jamain S, Jiménez E, Kahn JP, Kassem L, Kato T, Kelsoe J, Kittel-Schneider S, Kuo PH, Kusumi I, König B, Laje G, Landén M, Lavebratt C, Leboyer M, Leckband SG, Maj M, Manchia M, Marie-Claire C, Martinsson L, McCarthy MJ, McElroy SL, Millischer V, Mitjans M, Mondimore FM, Monteleone P, Nievergelt CM, Novák T, Nöthen MM, O'Donovan C, Ozaki N, Papiol S, Pfennig A, Pisanu C, Potash JB, Reif A, Reininghaus E, Richard-Lepouriel H, Roberts G, Rouleau GA, Rybakowski JK, Schalling M, Schofield PR, Schubert KO, Schulte EC, Schweizer BW, Severino G, Shekhtman T, Shilling PD, Shimoda K, Simhandl C, Slaney CM, Squassina A, Stamm T, Stopkova P, Streit F, Tekola-Ayele F, Thalamuthu A, Tortorella A, Turecki G, Veeh J, Vieta E, Viswanath B, Witt SH, Zandi PP, Alda M, Bauer M, McMahon FJ, Mitchell PB, Rietschel M, Schulze TG, and Baune BT
Abstract: Background: Lithium (Li) remains the treatment of choice for bipolar disorders (BP). Its mood-stabilizing effects help reduce the long-term burden of mania, depression and suicide risk in patients with BP. It also has been shown to have beneficial effects on disease-associated conditions, including sleep and cardiovascular disorders. However, the individual responses to Li treatment vary within and between diagnostic subtypes of BP (e.g. BP-I and BP-II) according to the clinical presentation. Moreover, long-term Li treatment has been linked to adverse side-effects that are a cause of concern and non-adherence, including the risk of developing chronic medical conditions such as thyroid and renal disease. In recent years, studies by the Consortium on Lithium Genetics (ConLiGen) have uncovered a number of genetic factors that contribute to the variability in Li treatment response in patients with BP. Here, we leveraged the ConLiGen cohort (N=2,064) to investigate the genetic basis of Li effects in BP. For this, we studied how Li response and linked genes associate with the psychiatric symptoms and polygenic load for medical comorbidities, placing particular emphasis on identifying differences between BP-I and BP-II., Results: We found that clinical response to Li treatment, measured with the Alda scale, was associated with a diminished burden of mania, depression, substance and alcohol abuse, psychosis and suicidal ideation in patients with BP-I and, in patients with BP-II, of depression only. Our genetic analyses showed that a stronger clinical response to Li was modestly related to lower polygenic load for diabetes and hypertension in BP-I but not BP-II. Moreover, our results suggested that a number of genes that have been previously linked to Li response variability in BP differentially relate to the psychiatric symptomatology, particularly to the numbers of manic and depressive episodes, and to the polygenic load for comorbid conditions, including diabetes, hypertension and hypothyroidism., Conclusions: Taken together, our findings suggest that the effects of Li on symptomatology and comorbidity in BP are partially modulated by common genetic factors, with differential effects between BP-I and BP-II., Competing Interests: Competing interests Eduard Vieta has received grants and served as consultant, advisor or CME speaker for the following entities: AB-Biotics, Abbvie, Almirall, Allergan, Angelini, AstraZeneca, Bristol-Myers Squibb, Dainippon Sumitomo Pharma, Farmindustria, Ferrer, Forest Research Institute, Gedeon Richter, GH Research, Glaxo-Smith-Kline, Janssen, Lundbeck, Orion, Otsuka, Pfizer, Roche, Rovi, Sanofi-Aventis, Servier, Shire, Sunovion, Takeda, the Brain and Behaviour Foundation, the Spanish Ministry of Science and Innovation (CIBERSAM), the Stanley Medical Research Institute and Viatris. Michael Bauer has received grants from the Deutsche Forschungsgemeinschaft (DFG), and Bundesministeriums für Bildung und Forschung (BMBF), and served as consultant, advisor or CME speaker for the following entities: Allergan, Aristo, Janssen, Lilly, Lundbeck, neuraxpharm, Otsuka, Sandoz, Servier and Sunovion outside the submitted work. Sarah Kittel-Schneider has received grants and served as consultant, advisor or speaker for the following entities: Medice Arzneimittel Pütter GmbH and Takeda. Bernhard Baune has received grants and served as consultant, advisor or CME speaker for the following entities: AstraZeneca, Bristol-Myers Squibb, Janssen, Lundbeck, Otsuka, Servier, the National Health and Medical Research Council, the Fay Fuller Foundation, the James and Diana Ramsay Foundation. Tadafumi Kato received honoraria for lectures, manuscripts, and/or consultancy, from Kyowa Hakko Kirin Co, Ltd, Eli Lilly Japan K.K., Otsuka Pharmaceutical Co, Ltd, GlaxoSmithKline K.K., Taisho Toyama Pharmaceutical Co, Ltd, Dainippon Sumitomo Pharma Co, Ltd, Meiji Seika Pharma Co, Ltd, Pfizer Japan Inc., Mochida Pharmaceutical Co, Ltd, Shionogi & Co, Ltd, Janssen Pharmaceutical K.K., Janssen Asia Pacific, Yoshitomiyakuhin, Astellas Pharma Inc, Wako Pure Chemical Industries, Ltd, Wiley Publishing Japan, Nippon Boehringer Ingelheim Co Ltd, Kanae Foundation for the Promotion of Medical Science, MSD K.K., Kyowa Pharmaceutical Industry Co, Ltd and Takeda Pharmaceutical Co, Ltd. Tadafumi Kato also received a research grant from Takeda Pharmaceutical Co, Ltd. Peter Falkai has received grants and served as consultant, advisor or CME speaker for the following entities Abbott, GlaxoSmithKline, Janssen, Essex, Lundbeck, Otsuka, Gedeon Richter, Servier and Takeda as well as the German Ministry of Science and the German Ministry of Health. Eva Reininghaus has received grants and served as consultant, advisor or CME speaker for the following entities: Janssen and Institut Allergosan. Mikael Landén has received lecture honoraria from Lundbeck. Kazufumi Akiyama has received consulting honoraria from Taisho Toyama Pharmaceutical Co, Ltd. Scott Clark has received grants, or data and served as consultant, advisor or CME speaker for the following entities: Otsuka Austalia, Lundbeck Australia, Janssen-Cilag Australia, Servier Australia,Viatris. Bruno Etain received honoraria from Sanofi Aventis. The rest of authors have no conflicts of interest to disclose.
Published: 2023
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37. MTOR gene variants are associated with severe COVID-19 outcomes: A multicenter study.

Author: Tosta BR, de Almeida IM, da Cruz Pena L, Dos Santos Silva H, Reis-Goes FS, Silva NN, Cruz JVA, Dos Anjos Silva M, de Araújo JF, Rodrigues JL, Oliveira G, Figueiredo RG, Vaz SN, Montaño-Castellón I, Santana D, de Lima Beltrão FE, Carneiro VL, Campos GS, Brites C, Fortuna V, Figueiredo CA, Trindade SC, Ramos HE, and Costa RDS
Subjects: Humans, Patient Acuity, Case-Control Studies, Male, Female, Adult, Middle Aged, Aged, Survival Analysis, Cytokines blood, Genetic Variation, COVID-19 genetics, COVID-19 immunology, COVID-19 mortality, COVID-19 pathology, TOR Serine-Threonine Kinases genetics
Abstract: Background: The worst outcomes linked to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have been attributed to the cytokine storm, which contributes significantly to the immunopathogenesis of the disease. The mammalian target of rapamycin (mTOR) pathway is essential for orchestrating innate immune cell defense including cytokine production and is dysregulated in severe Coronavirus Disease 2019 (COVID-19) individuals. The individual genetic background might play a role in the exacerbated immune response., Objective: In this study, we aimed to investigate the association between MTOR genetic variants and COVID-19 outcomes., Methods: This study enrolled groups of individuals with severe (n = 285) and mild (n = 207) COVID-19 from Brazilian states. The MTOR variants, rs1057079 and rs2536, were genotyped. A logistic regression analysis and Kaplan-Meier survival curves were performed. We applied a genotyping risk score to estimate the cumulative contribution of the risk alleles. Tumor necrosis factor (TNF) and interleukin-6 (IL-6) plasma levels were also measured., Results: The T allele of the MTOR rs1057079 variant was associated with a higher likelihood of developing the most severe form of COVID-19. In addition, higher levels of IL-6 and COVID-19 death was linked to the T allele of the rs2536 variant. These variants exhibited a cumulative risk when inherited collectively., Conclusions: These results show a potential pathogenetic role of MTOR gene variants and may be useful for predicting severe outcomes following COVID-19 infection, resulting in a more effective allocation of health resources., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)
Published: 2023
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38. Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder.

Author: Amare AT, Thalamuthu A, Schubert KO, Fullerton JM, Ahmed M, Hartmann S, Papiol S, Heilbronner U, Degenhardt F, Tekola-Ayele F, Hou L, Hsu YH, Shekhtman T, Adli M, Akula N, Akiyama K, Ardau R, Arias B, Aubry JM, Hasler R, Richard-Lepouriel H, Perroud N, Backlund L, Bhattacharjee AK, Bellivier F, Benabarre A, Bengesser S, Biernacka JM, Birner A, Marie-Claire C, Cervantes P, Chen HC, Chillotti C, Cichon S, Cruceanu C, Czerski PM, Dalkner N, Del Zompo M, DePaulo JR, Étain B, Jamain S, Falkai P, Forstner AJ, Frisen L, Frye MA, Gard S, Garnham JS, Goes FS, Grigoroiu-Serbanescu M, Fallgatter AJ, Stegmaier S, Ethofer T, Biere S, Petrova K, Schuster C, Adorjan K, Budde M, Heilbronner M, Kalman JL, Kohshour MO, Reich-Erkelenz D, Schaupp SK, Schulte EC, Senner F, Vogl T, Anghelescu IG, Arolt V, Dannlowski U, Dietrich D, Figge C, Jäger M, Lang FU, Juckel G, Konrad C, Reimer J, Schmauß M, Schmitt A, Spitzer C, von Hagen M, Wiltfang J, Zimmermann J, Andlauer TFM, Fischer A, Bermpohl F, Ritter P, Matura S, Gryaznova A, Falkenberg I, Yildiz C, Kircher T, Schmidt J, Koch M, Gade K, Trost S, Haussleiter IS, Lambert M, Rohenkohl AC, Kraft V, Grof P, Hashimoto R, Hauser J, Herms S, Hoffmann P, Jiménez E, Kahn JP, Kassem L, Kuo PH, Kato T, Kelsoe J, Kittel-Schneider S, Ferensztajn-Rochowiak E, König B, Kusumi I, Laje G, Landén M, Lavebratt C, Leboyer M, Leckband SG, Tortorella A, Manchia M, Martinsson L, McCarthy MJ, McElroy S, Colom F, Millischer V, Mitjans M, Mondimore FM, Monteleone P, Nievergelt CM, Nöthen MM, Novák T, O'Donovan C, Ozaki N, Pfennig A, Pisanu C, Potash JB, Reif A, Reininghaus E, Rouleau GA, Rybakowski JK, Schalling M, Schofield PR, Schweizer BW, Severino G, Shilling PD, Shimoda K, Simhandl C, Slaney CM, Squassina A, Stamm T, Stopkova P, Maj M, Turecki G, Vieta E, Veeh J, Witt SH, Wright A, Zandi PP, Mitchell PB, Bauer M, Alda M, Rietschel M, McMahon FJ, Schulze TG, Clark SR, and Baune BT
Subjects: Humans, Female, Male, Adult, Middle Aged, Treatment Outcome, Bayes Theorem, Genome-Wide Association Study methods, Glutamic Acid metabolism, Cohort Studies, Lithium Compounds therapeutic use, Lithium Compounds pharmacology, Acetylcholine metabolism, Polymorphism, Single Nucleotide genetics, Antimanic Agents therapeutic use, Antimanic Agents pharmacology, Bipolar Disorder drug therapy, Bipolar Disorder genetics, Multifactorial Inheritance genetics, Lithium therapeutic use, Lithium pharmacology
Abstract: Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental health disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li + PGS ) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li + PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi + Gen: N = 2367) and replicated in the combined PsyCourse (N = 89) and BipoLife (N = 102) studies. The associations of Li + PGS and lithium treatment response - defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P < 0.05. Li + PGS was positively associated with lithium treatment response in the ConLi + Gen cohort, in both the categorical (P = 9.8 × 10 - 12 , R 2 = 1.9%) and continuous (P = 6.4 × 10 - 9 , R 2 = 2.6%) outcomes. Compared to bipolar patients in the 1 st decile of the risk distribution, individuals in the 10 th decile had 3.47-fold (95%CI: 2.22-5.47) higher odds of responding favorably to lithium. The results were replicated in the independent cohorts for the categorical treatment outcome (P = 3.9 × 10 - 4 , R 2 = 0.9%), but not for the continuous outcome (P = 0.13). Gene-based analyses revealed 36 candidate genes that are enriched in biological pathways controlled by glutamate and acetylcholine. Li + PGS may be useful in the development of pharmacogenomic testing strategies by enabling a classification of bipolar patients according to their response to treatment., (© 2023. The Author(s).)
Published: 2023
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39. Genome-wide significant risk loci for mood disorders in the Old Order Amish founder population.

Author: Humphries EM, Ahn K, Kember RL, Lopes FL, Mocci E, Peralta JM, Blangero J, Glahn DC, Goes FS, Zandi PP, Kochunov P, Van Hout C, Shuldiner AR, Pollin TI, Mitchell BD, Bucan M, Hong LE, McMahon FJ, and Ament SA
Subjects: Humans, Male, Female, Middle Aged, Adult, Case-Control Studies, Transcription Factors genetics, Risk Factors, Genetic Loci, Repressor Proteins genetics, Aged, Homeodomain Proteins genetics, Founder Effect, Nuclear Proteins genetics, Genome-Wide Association Study methods, Genetic Predisposition to Disease genetics, Mood Disorders genetics, Polymorphism, Single Nucleotide genetics, Amish genetics
Abstract: Genome-wide association studies (GWAS) of mood disorders in large case-control cohorts have identified numerous risk loci, yet pathophysiological mechanisms remain elusive, primarily due to the very small effects of common variants. We sought to discover risk variants with larger effects by conducting a genome-wide association study of mood disorders in a founder population, the Old Order Amish (OOA, n = 1,672). Our analysis revealed four genome-wide significant risk loci, all of which were associated with >2-fold relative risk. Quantitative behavioral and neurocognitive assessments (n = 314) revealed effects of risk variants on sub-clinical depressive symptoms and information processing speed. Network analysis suggested that OOA-specific risk loci harbor novel risk-associated genes that interact with known neuropsychiatry-associated genes via gene interaction networks. Annotation of the variants at these risk loci revealed population-enriched, non-synonymous variants in two genes encoding neurodevelopmental transcription factors, CUX1 and CNOT1. Our findings provide insight into the genetic architecture of mood disorders and a substrate for mechanistic and clinical studies., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)
Published: 2023
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40. Brain-based correlates of antidepressant response to ketamine: a comprehensive systematic review of neuroimaging studies.

Author: Medeiros GC, Matheson M, Demo I, Reid MJ, Matheson S, Twose C, Smith GS, Gould TD, Zarate CA Jr, Barrett FS, and Goes FS
Subjects: Humans, Brain diagnostic imaging, Antidepressive Agents therapeutic use, Antidepressive Agents pharmacology, Neuroimaging, Biomarkers, Ketamine therapeutic use
Abstract: Ketamine is an effective antidepressant, but there is substantial variability in patient response and the precise mechanism of action is unclear. Neuroimaging can provide predictive and mechanistic insights, but findings are limited by small sample sizes. This systematic review covers neuroimaging studies investigating baseline (pre-treatment) and longitudinal (post-treatment) biomarkers of responses to ketamine. All modalities were included. We performed searches of five electronic databases (from inception to April 26, 2022). 69 studies were included (with 1751 participants). There was substantial methodological heterogeneity and no well replicated biomarker. However, we found convergence across some significant results, particularly in longitudinal biomarkers. Response to ketamine was associated with post-treatment increases in gamma power in frontoparietal regions in electrophysiological studies, post-treatment increases in functional connectivity within the prefrontal cortex, and post-treatment increases in the functional activation of the striatum. Although a well replicated neuroimaging biomarker of ketamine response was not identified, there are biomarkers that warrant further investigation., Competing Interests: Declaration of interests GSS conducted an investigator-initiated study that used medication (vortioxetine) provided without charge by Lundbeck. TDG is listed as coauthor on patent and patent applications related to the pharmacology and use of (2R,6R)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and post-traumatic stress disorder. He has assigned his patent rights to the University of Maryland, Baltimore, but will share a percentage of any royalties that might be received. TDG has also received research funding from Allergan and Roche Pharmaceuticals. CAZ is listed as a co-inventor on a patent for the use of ketamine in major depression and suicidal ideation; as a co-inventor on a patent for the use of (2R,6R)-hydroxynorketamine, (S)-dehydronorketamine, and other stereoisomeric dehydroxylated and hydroxylated metabolites of (R,S)-ketamine metabolites in the treatment of depression and neuropathic pain; and as a co-inventor on a patent application for the use of (2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and post-traumatic stress disorders. He has assigned his patent rights to the US Government but will share a percentage of any royalties that might be received. FSB is a scientific adviser for WavePaths, and MindState Design Labs. FSG has received research grant support from Janssen Therapeutics. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)
Published: 2023
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41. Exploring dysregulated immune response genes and endothelial dysfunction biomarkers as predictors of severe COVID-19.

Author: Reis-Goes FS, Silva NN, Gondim TM, Figueiredo RG, Evangelista GAO, Marchioro SB, Costa RS, Torres AJL, Meyer RJ, Trindade SC, and Fortuna V
Subjects: Male, Humans, P-Selectin metabolism, Platelet Count, Biomarkers, Neutrophils metabolism, Immunity, Retrospective Studies, COVID-19 metabolism, Vascular Diseases
Abstract: Identifying individuals and factors associated with severe cases of COVID-19 is crucial as the pandemic continues to spread globally. Effective biomarkers for predicting severe cases are essential for optimizing clinical management, therapy, and preventing unfavorable outcomes. This exploratory observational study aimed to investigate the expression of dysregulated immune response genes (ARG1, NOS2, ITGA4, and SELPLG) in total leukocytes, plasmatic levels of P-selectin and PSGL-1, and their clinical associations in patients with mild and severe COVID-19. Data from 117 confirmed COVID-19 patients (severe = 58, mild = 59) were collected upon admission. Gene expression was measured using RT-qPCR, and plasma protein levels assessed with ELISA assay. The severe COVID-19 patient group had a higher median age of 62.0 (p = 0.0001), a higher proportion of black individuals (86.2%, p < 0.0001), and more males (65.5%, p = 0.007). The neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) were significantly higher in the severe COVID-19 patient group (p < 0.0001), indicating ongoing systemic inflammation. Severe COVID-19 patients also exhibited increased expression of ARG1 (p < 0.05) and SELPLG (p < 0.0001) genes, as well as higher concentrations of soluble P-selectin (p < 0.005) and PSGL-1 (p < 0.05) proteins. Multivariate analysis revealed that NLR, PLR, the expression of SELPLG and sPSGL-1 were independent predictors of COVID-19 severity. In conclusion, this study suggests that biomarkers of endothelial dysfunction and dysregulated leukocyte responses are associated with COVID-19 severity, serving as promising predictive tools for optimizing clinical management and patient monitoring., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)
Published: 2023
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42. Ketamine versus ECT for Nonpsychotic Treatment-Resistant Major Depression.

Author: Anand A, Mathew SJ, Sanacora G, Murrough JW, Goes FS, Altinay M, Aloysi AS, Asghar-Ali AA, Barnett BS, Chang LC, Collins KA, Costi S, Iqbal S, Jha MK, Krishnan K, Malone DA, Nikayin S, Nissen SE, Ostroff RB, Reti IM, Wilkinson ST, Wolski K, and Hu B
Subjects: Humans, Depressive Disorder, Major diagnosis, Depressive Disorder, Major drug therapy, Depressive Disorder, Major therapy, Quality of Life, Treatment Outcome, Administration, Intravenous, Psychotic Disorders, Electroconvulsive Therapy adverse effects, Ketamine administration & dosage, Ketamine adverse effects, Ketamine therapeutic use, Antidepressive Agents administration & dosage, Antidepressive Agents adverse effects, Antidepressive Agents therapeutic use, Depressive Disorder, Treatment-Resistant diagnosis, Depressive Disorder, Treatment-Resistant drug therapy, Depressive Disorder, Treatment-Resistant therapy
Abstract: Background: Electroconvulsive therapy (ECT) and subanesthetic intravenous ketamine are both currently used for treatment-resistant major depression, but the comparative effectiveness of the two treatments remains uncertain., Methods: We conducted an open-label, randomized, noninferiority trial involving patients referred to ECT clinics for treatment-resistant major depression. Patients with treatment-resistant major depression without psychosis were recruited and assigned in a 1:1 ratio to receive ketamine or ECT. During an initial 3-week treatment phase, patients received either ECT three times per week or ketamine (0.5 mg per kilogram of body weight over 40 minutes) twice per week. The primary outcome was a response to treatment (i.e., a decrease of ≥50% from baseline in the score on the 16-item Quick Inventory of Depressive Symptomatology-Self-Report; scores range from 0 to 27, with higher scores indicating greater depression). The noninferiority margin was -10 percentage points. Secondary outcomes included scores on memory tests and patient-reported quality of life. After the initial treatment phase, the patients who had a response were followed over a 6-month period., Results: A total of 403 patients underwent randomization at five clinical sites; 200 patients were assigned to the ketamine group and 203 to the ECT group. After 38 patients had withdrawn before initiation of the assigned treatment, ketamine was administered to 195 patients and ECT to 170 patients. A total of 55.4% of the patients in the ketamine group and 41.2% of those in the ECT group had a response (difference, 14.2 percentage points; 95% confidence interval, 3.9 to 24.2; P<0.001 for the noninferiority of ketamine to ECT). ECT appeared to be associated with a decrease in memory recall after 3 weeks of treatment (mean [±SE] decrease in the T-score for delayed recall on the Hopkins Verbal Learning Test-Revised, -0.9±1.1 in the ketamine group vs. -9.7±1.2 in the ECT group; scores range from -300 to 200, with higher scores indicating better function) with gradual recovery during follow-up. Improvement in patient-reported quality-of-life was similar in the two trial groups. ECT was associated with musculoskeletal adverse effects, whereas ketamine was associated with dissociation., Conclusions: Ketamine was noninferior to ECT as therapy for treatment-resistant major depression without psychosis. (Funded by the Patient-Centered Outcomes Research Institute; ELEKT-D ClinicalTrials.gov number, NCT03113968.)., (Copyright © 2023 Massachusetts Medical Society.)
Published: 2023
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43. Racial differences in the major clinical symptom domains of bipolar disorder.

Author: Li K, Richards E, and Goes FS
Abstract: Background: Across clinical settings, black individuals are disproportionately less likely to be diagnosed with bipolar disorder compared to schizophrenia, a traditionally more severe and chronic disorder with lower expectations for remission. The causes of this disparity are likely multifactorial, ranging from the effects of implicit bias, to developmental and lifelong effects of structural racism, to differing cultural manifestations of psychiatric symptoms and distress. While prior studies examining differences have found a greater preponderance of specific psychotic symptoms (such as persecutory delusions and hallucinations) and a more dysphoric/mixed mania presentation in Black individuals, these studies have been limited by a lack of systematic phenotypic assessment and small sample sizes. In the current report, we have combined data from two large multi-ethnic studies of bipolar disorder with comparable semi-structured interviews to investigate differences in symptoms presentation across the major clinical symptom domains of bipolar disorder., Results: In the combined meta-analysis, there were 4423 patients diagnosed with bipolar disorder type I, including 775 of self-reported as Black race. When symptom presentations were compared in Black versus White individuals, differences were found across all the major clinical symptom domains of bipolar disorder. Psychotic symptoms, particularly persecutory hallucinations and both persecutory and mood-incongruent delusions, were more prevalent in Black individuals with bipolar disorder type I (ORs = 1.26 to 2.45). In contrast, Black individuals endorsed fewer prototypical manic symptoms, with a notably decreased likelihood of endorsing abnormally elevated mood (OR = 0.44). Within depression associated symptoms, we found similar rates of mood or cognitive related mood symptoms but higher rates of decreased appetite (OR = 1.32) and weight loss (OR = 1.40), as well as increased endorsement of initial, middle, and early-morning insomnia (ORs = 1.73 to 1.82). Concurrently, we found that black individuals with BP-1 were much less likely to be treated with mood stabilizers, such as lithium (OR = 0.45), carbamazepine (OR = 0.37) and lamotrigine (OR = 0.34), and moderately more likely to be on antipsychotic medications (OR = 1.25)., Conclusions: In two large studies spanning over a decade, we found highly consistent and enduring differences in symptoms across the major clinical symptom domains of bipolar disorder. These differences were marked by a greater burden of mood-incongruent psychotic symptoms, insomnia and irritability, and fewer prototypical symptoms of mania. While such symptoms warrant better recognition to reduce diagnostic disparities, they may also represent potential targets of treatment that can be addressed to mitigate persistent disparities in outcome., (© 2023. The Author(s).)
Published: 2023
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44. Prevalence and correlates of lifetime suicide attempt in obsessive-compulsive disorder with major depression.

Author: Samuels J, Bienvenu OJ, Krasnow J, Grados MA, Cullen BA, Goes FS, McLaughlin NC, Rasmussen SA, Fyer AJ, Knowles JA, McCracken JT, Geller D, Riddle MA, Piacentini J, Stewart SE, Greenberg BD, Nestadt G, and Nestadt P
Subjects: Adult, Male, Humans, Child, Suicide, Attempted, Depression, Prevalence, Prospective Studies, Comorbidity, Depressive Disorder, Major epidemiology, Obsessive-Compulsive Disorder epidemiology
Abstract: Background: Little is known about specific obsessive-compulsive clinical features associated with lifetime history of suicide attempt in individuals with obsessive-compulsive disorder (OCD) and major depression., Methods: The study sample included 515 adults with OCD and a history of major depression. In exploratory analyses, we compared the distributions of demographic characteristics and clinical features in those with and without a history of attempted suicide and used logistic regression to evaluate the association between specific obsessive-compulsive clinical features and lifetime suicide attempt., Results: Sixty-four (12%) of the participants reported a lifetime history of suicide attempt. Those who had attempted suicide were more likely to report having experienced violent or horrific images (52% vs. 30%; p < 0.001). The odds of lifetime suicide attempt were more than twice as great in participants with versus without violent or horrific images (O.R. = 2.46, 95%, CI = 1.45-4.19; p < 0.001), even after adjustment for other risk correlates of attempted suicide, including alcohol dependence, post-traumatic stress disorder, parental conflict, excessive physical discipline, and number of episodes of depression. The association between violent or horrific images and attempted suicide was especially strong in men, 18-29 year olds, those with post-traumatic stress disorder, and those with particular childhood adversities., Conclusions: Violent or horrific images are strongly associated with lifetime suicide attempts in OCD-affected individuals with a history of major depression. Prospective clinical and epidemiological studies are needed to elucidate the basis of this relationship., Competing Interests: Declaration of competing interest The authors have no conflict of interest to declare., (Copyright © 2023 Elsevier Ltd. All rights reserved.)
Published: 2023
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45. Diagnosis and management of bipolar disorders.

Author: Goes FS
Subjects: Young Adult, Humans, Combined Modality Therapy, Bipolar Disorder diagnosis, Bipolar Disorder drug therapy, Antipsychotic Agents adverse effects
Abstract: Bipolar disorders (BDs) are recurrent and sometimes chronic disorders of mood that affect around 2% of the world's population and encompass a spectrum between severe elevated and excitable mood states (mania) to the dysphoria, low energy, and despondency of depressive episodes. The illness commonly starts in young adults and is a leading cause of disability and premature mortality. The clinical manifestations of bipolar disorder can be markedly varied between and within individuals across their lifespan. Early diagnosis is challenging and misdiagnoses are frequent, potentially resulting in missed early intervention and increasing the risk of iatrogenic harm. Over 15 approved treatments exist for the various phases of bipolar disorder, but outcomes are often suboptimal owing to insufficient efficacy, side effects, or lack of availability. Lithium, the first approved treatment for bipolar disorder, continues to be the most effective drug overall, although full remission is only seen in a subset of patients. Newer atypical antipsychotics are increasingly being found to be effective in the treatment of bipolar depression; however, their long term tolerability and safety are uncertain. For many with bipolar disorder, combination therapy and adjunctive psychotherapy might be necessary to treat symptoms across different phases of illness. Several classes of medications exist for treating bipolar disorder but predicting which medication is likely to be most effective or tolerable is not yet possible. As pathophysiological insights into the causes of bipolar disorders are revealed, a new era of targeted treatments aimed at causal mechanisms, be they pharmacological or psychosocial, will hopefully be developed. For the time being, however, clinical judgment, shared decision making, and empirical follow-up remain essential elements of clinical care. This review provides an overview of the clinical features, diagnostic subtypes, and major treatment modalities available to treat people with bipolar disorder, highlighting recent advances and ongoing therapeutic challenges., Competing Interests: Competing interests: I have read and understood the BMJ policy on declaration of interests and declare no conflicts of interest., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)
Published: 2023
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46. κ-Opioid Receptor Plasma Levels Are Associated With Sex and Diagnosis of Major Depressive Disorder But Not Response to Ketamine.

Author: Quintanilla B, Medeiros GC, Greenstein D, Yuan P, Johnston JN, Park LT, Goes FS, Gould TD, and Zarate CA Jr
Subjects: Male, Humans, Female, Receptors, Opioid, kappa therapeutic use, Dynorphins therapeutic use, Antidepressive Agents therapeutic use, Depressive Disorder, Major drug therapy, Ketamine therapeutic use
Abstract: Background: Preclinical evidence indicates that the κ-opioid receptor (KOR)/dynorphin pathway is implicated in depressive-like behaviors. Ketamine is believed to partly exert its antidepressant effects by modulating the opioid system. This post hoc study examined the following research questions: (1) at baseline, were there differences in KOR or dynorphin plasma levels between individuals with major depressive disorder (MDD) and healthy volunteers (HVs) or between men and women? (2) in individuals with MDD, did KOR or dynorphin baseline plasma levels moderate ketamine's therapeutic effects or adverse effects? and (3) in individuals with MDD, were KOR or dynorphin plasma levels affected after treatment with ketamine compared with placebo?, Methods: Thirty-nine unmedicated individuals with MDD (23 women) and 25 HVs (16 women) received intravenous ketamine (0.5 mg/kg) and placebo in a randomized, crossover, double-blind trial. Blood was obtained from all participants at baseline and at 3 postinfusion time points (230 minutes, day 1, day 3). Linear mixed model regressions were used., Results: At baseline, participants with MDD had lower KOR plasma levels than HVs ( F1,60 = 13.16, P < 0.001), and women (MDD and HVs) had higher KOR plasma levels than men ( F1,60 = 4.98, P = 0.03). Diagnosis and sex had no significant effects on baseline dynorphin levels. Baseline KOR and dynorphin levels did not moderate ketamine's therapeutic or adverse effects. Compared with placebo, ketamine was not associated with postinfusion changes in KOR or dynorphin levels., Conclusions: In humans, diagnosis of MDD and biological sex are involved with changes in components of the KOR/dynorphin pathway. Neither KOR nor dynorphin levels consistently moderated ketamine's therapeutic effects or adverse effects, nor were levels altered after ketamine infusion., Trial Registration: NCT00088699 ( ClinicalTrials.gov )., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)
Published: 2023
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47. Corrigendum to "The PHQ-9 item 9 based screening for suicide risk: A validation study of the patient health questionnaire (PHQ)-9 item 9 with the Columbia suicide severity rating scale (C-SSRS)" [J. Affect. Disord. 232 (2018) 34-40].

Author: Na PJ, Yaramala SR, Kim JA, Kim H, Goes FS, Zandi PP, Vande Voort JL, Sutor B, Croarkin PE, and Bobo WV
Published: 2023
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48. Patients' recovery and non-recovery narratives after intravenous ketamine for treatment-resistant depression.

Author: Lapidos A, Lopez-Vives D, Sera CE, Ahearn E, Vest E, Senic I, Vande Voort JL, Frye M, Goes FS, Achtyes E, Greden J, and Parikh SV
Subjects: Adult, Humans, Antidepressive Agents therapeutic use, Depression drug therapy, Infusions, Intravenous, Treatment Outcome, Depressive Disorder, Treatment-Resistant drug therapy, Hallucinogens therapeutic use, Ketamine therapeutic use
Abstract: Background: Intravenous (IV) ketamine is an effective therapy for treatment-resistant depression. A large data base is confirmatory and steadily expanding. Qualitative studies can inform best practices and suggest new research directions. As part of a clinical trial designed to identify biomarkers of ketamine response, a qualitative study was conducted to characterize experiences with: receiving infusions; recovering or not recovering from depression; and beliefs about why ketamine worked or did not work., Methods: Adults with treatment-resistant depression received three IV ketamine infusions in a two-week period and were characterized as remitters or non-remitters via symptom reduction 24 h after the third infusion. Qualitative interviews of a subset of participants were audio recorded, transcribed verbatim, and coded using deductive and inductive methods. Themes were derived and compared across a broader construct of recovery status., Results: Of the 21 participants, nine (43 %) were characterized as having experienced remission and 12 (57 %) non-remission. Of the 12 non-remitters, five were characterized as having experienced partial recovery based on their subjective experiences, reporting substantial benefit from ketamine infusions despite non-remission status based on scale measurements. Attributions for ketamine's effects included biological and experiential mechanisms. Among non-remitters there was risk of disappointment when adding another failed treatment., Limitations: A more diverse sample may have yielded different themes. Different patients had different amounts of time elapsed between ketamine infusions and qualitative interview., Conclusions: Qualitative methods may enhance researchers' characterization of IV ketamine's impact on treatment-resistant depression. While requiring confirmation, patients may benefit from a preparatory milieu that prepares them for multiple recovery pathways; decouples the psychedelic experience from clinical outcomes; and addresses potential risks of another failed treatment., Competing Interests: Declaration of competing interest Adrienne Lapidos, Daniela Lopez-Vives, Cortney E. Sera, Elizabeth Ahearn, Erica Vest, Ivana Senic, and John Greden have no conflicts of interest to declare. Dr. Vande Voort has received grant-in-kind support for supplies and genotyping from Assurex Health. Dr. Frye has received grant support from Assurex Health, and Mayo Foundation. He also has financial interests in Chymia LLC. Dr. Goes has received research grant support from Janssen Therapeutics. Dr. Achtyes has served on advisory boards or consulted for Alkermes, Atheneum, Janssen, Karuna, Lundbeck/Otsuka, Roche, Sunovion and Teva and reports previous stock holdings in AstraZeneca, Johnson & Johnson, Moderna, and Pfizer. Dr. Achtyes has received research support from Alkermes, Astellas, Biogen, Boehringer-Ingelheim, InnateVR, Janssen, National Network of Depression Centers, Neurocrine Biosciences, Novartis, Otsuka, Pear Therapeutics, and Takeda. Dr. Achtyes serves as an advisor to CAPNOS Zero, the World Psychiatric Association and Clubhouse International, and the SMI Adviser LAI Center of Excellence (all unpaid). Dr. Parikh has received honoraria for consulting or research funds from Assurex (Myriad), Sage, Otsuka, Takeda, Janssen, Aifred, Mensante, Canadian Institutes for Health Research, Ontario Brain Institute, and the Flinn Foundation., (Copyright © 2022 Elsevier B.V. All rights reserved.)
Published: 2023
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49. Investigating the phenotypic and genetic associations between personality traits and suicidal behavior across major mental health diagnoses.

Author: Kalman JL, Yoshida T, Andlauer TFM, Schulte EC, Adorjan K, Alda M, Ardau R, Aubry JM, Brosch K, Budde M, Chillotti C, Czerski PM, DePaulo RJ, Forstner A, Goes FS, Grigoroiu-Serbanescu M, Grof P, Grotegerd D, Hahn T, Heilbronner M, Hasler R, Heilbronner U, Heilmann-Heimbach S, Kapelski P, Kato T, Kohshour MO, Meinert S, Meller T, Nenadić I, Nöthen MM, Novak T, Opel N, Pawlak J, Pfarr JK, Potash JB, Reich-Erkelenz D, Repple J, Richard-Lepouriel H, Rietschel M, Ringwald KG, Rouleau G, Schaupp S, Senner F, Severino G, Squassina A, Stein F, Stopkova P, Streit F, Thiel K, Thomas-Odenthal F, Turecki G, Twarowska-Hauser J, Winter A, Zandi PP, Kelsoe JR, Falkai P, Dannlowski U, Kircher T, Schulze TG, and Papiol S
Subjects: Humans, Mental Health, Personality genetics, Phenotype, Suicidal Ideation, Depressive Disorder, Major psychology
Abstract: Personality traits influence risk for suicidal behavior. We examined phenotype- and genotype-level associations between the Big Five personality traits and suicidal ideation and attempt in major depressive, bipolar and schizoaffective disorder, and schizophrenia patients (N = 3012) using fixed- and random-effects inverse variance-weighted meta-analyses. Suicidal ideations were more likely to be reported by patients with higher neuroticism and lower extraversion phenotypic scores, but showed no significant association with polygenic load for these personality traits. Our findings provide new insights into the association between personality and suicidal behavior across mental illnesses and suggest that the genetic component of personality traits is unlikely to have strong causal effects on suicidal behavior., (© 2022. The Author(s).)
Published: 2022
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50. Blood-based biomarkers of antidepressant response to ketamine and esketamine: A systematic review and meta-analysis.

Author: Medeiros GC, Gould TD, Prueitt WL, Nanavati J, Grunebaum MF, Farber NB, Singh B, Selvaraj S, Machado-Vieira R, Achtyes ED, Parikh SV, Frye MA, Zarate CA Jr, and Goes FS
Subjects: Humans, Brain-Derived Neurotrophic Factor metabolism, Antidepressive Agents therapeutic use, Biomarkers, Ketamine pharmacology, Ketamine therapeutic use, Depressive Disorder, Treatment-Resistant drug therapy
Abstract: (R,S)-ketamine (ketamine) and its enantiomer (S)-ketamine (esketamine) can produce rapid and substantial antidepressant effects. However, individual response to ketamine/esketamine is variable, and there are no well-accepted methods to differentiate persons who are more likely to benefit. Numerous potential peripheral biomarkers have been reported, but their current utility is unclear. We conducted a systematic review/meta-analysis examining the association between baseline levels and longitudinal changes in blood-based biomarkers, and response to ketamine/esketamine. Of the 5611 citations identified, 56 manuscripts were included (N = 2801 participants), and 26 were compatible with meta-analytical calculations. Random-effect models were used, and effect sizes were reported as standardized mean differences (SMD). Our assessments revealed that more than 460 individual biomarkers were examined. Frequently studied groups included neurotrophic factors (n = 15), levels of ketamine and ketamine metabolites (n = 13), and inflammatory markers (n = 12). There were no consistent associations between baseline levels of blood-based biomarkers, and response to ketamine. However, in a longitudinal analysis, ketamine responders had statistically significant increases in brain-derived neurotrophic factor (BDNF) when compared to pre-treatment levels (SMD [95% CI] = 0.26 [0.03, 0.48], p = 0.02), whereas non-responders showed no significant changes in BDNF levels (SMD [95% CI] = 0.05 [-0.19, 0.28], p = 0.70). There was no consistent evidence to support any additional longitudinal biomarkers. Findings were inconclusive for esketamine due to the small number of studies (n = 2). Despite a diverse and substantial literature, there is limited evidence that blood-based biomarkers are associated with response to ketamine, and no current evidence of clinical utility., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
Published: 2022
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