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372 results on '"Kittel-Schneider, S."'

1. Genome-wide association study of borderline personality disorder reveals genetic overlap with bipolar disorder, major depression and schizophrenia.

Author

Witt, SH, Streit, F, Jungkunz, M, Frank, J, Awasthi, S, Reinbold, CS, Treutlein, J, Degenhardt, F, Forstner, AJ, Heilmann-Heimbach, S, Dietl, L, Schwarze, CE, Schendel, D, Strohmaier, J, Abdellaoui, A, Adolfsson, R, Air, TM, Akil, H, Alda, M, Alliey-Rodriguez, N, Andreassen, OA, Babadjanova, G, Bass, NJ, Bauer, M, Baune, BT, Bellivier, F, Bergen, S, Bethell, A, Biernacka, JM, Blackwood, DHR, Boks, MP, Boomsma, DI, Børglum, AD, Borrmann-Hassenbach, M, Brennan, P, Budde, M, Buttenschøn, HN, Byrne, EM, Cervantes, P, Clarke, T-K, Craddock, N, Cruceanu, C, Curtis, D, Czerski, PM, Dannlowski, U, Davis, T, de Geus, EJC, Di Florio, A, Djurovic, S, Domenici, E, Edenberg, HJ, Etain, B, Fischer, SB, Forty, L, Fraser, C, Frye, MA, Fullerton, JM, Gade, K, Gershon, ES, Giegling, I, Gordon, SD, Gordon-Smith, K, Grabe, HJ, Green, EK, Greenwood, TA, Grigoroiu-Serbanescu, M, Guzman-Parra, J, Hall, LS, Hamshere, M, Hauser, J, Hautzinger, M, Heilbronner, U, Herms, S, Hitturlingappa, S, Hoffmann, P, Holmans, P, Hottenga, J-J, Jamain, S, Jones, I, Jones, LA, Juréus, A, Kahn, RS, Kammerer-Ciernioch, J, Kirov, G, Kittel-Schneider, S, Kloiber, S, Knott, SV, Kogevinas, M, Landén, M, Leber, M, Leboyer, M, Li, QS, Lissowska, J, Lucae, S, Martin, NG, Mayoral-Cleries, F, McElroy, SL, McIntosh, AM, McKay, JD, and McQuillin, A

Subjects
Bipolar Disorders Working Group of the Psychiatric Genomics Consortium, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Humans, Genetic Predisposition to Disease, Case-Control Studies, Bipolar Disorder, Depressive Disorder, Major, Borderline Personality Disorder, Schizophrenia, Genotype, Multifactorial Inheritance, Adolescent, Adult, Aged, Middle Aged, Female, Male, Genome-Wide Association Study, Young Adult, Depressive Disorder, Major, Clinical Sciences, Public Health and Health Services, Psychology
Abstract

Borderline personality disorder (BOR) is determined by environmental and genetic factors, and characterized by affective instability and impulsivity, diagnostic symptoms also observed in manic phases of bipolar disorder (BIP). Up to 20% of BIP patients show comorbidity with BOR. This report describes the first case-control genome-wide association study (GWAS) of BOR, performed in one of the largest BOR patient samples worldwide. The focus of our analysis was (i) to detect genes and gene sets involved in BOR and (ii) to investigate the genetic overlap with BIP. As there is considerable genetic overlap between BIP, major depression (MDD) and schizophrenia (SCZ) and a high comorbidity of BOR and MDD, we also analyzed the genetic overlap of BOR with SCZ and MDD. GWAS, gene-based tests and gene-set analyses were performed in 998 BOR patients and 1545 controls. Linkage disequilibrium score regression was used to detect the genetic overlap between BOR and these disorders. Single marker analysis revealed no significant association after correction for multiple testing. Gene-based analysis yielded two significant genes: DPYD (P=4.42 × 10-7) and PKP4 (P=8.67 × 10-7); and gene-set analysis yielded a significant finding for exocytosis (GO:0006887, PFDR=0.019; FDR, false discovery rate). Prior studies have implicated DPYD, PKP4 and exocytosis in BIP and SCZ. The most notable finding of the present study was the genetic overlap of BOR with BIP (rg=0.28 [P=2.99 × 10-3]), SCZ (rg=0.34 [P=4.37 × 10-5]) and MDD (rg=0.57 [P=1.04 × 10-3]). We believe our study is the first to demonstrate that BOR overlaps with BIP, MDD and SCZ on the genetic level. Whether this is confined to transdiagnostic clinical symptoms should be examined in future studies.

Published
2017

3. 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 ; https://orcid.org/0000-0003-4014-4490, 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 ; https://orcid.org/0000-0002-1966-5120, Rouleau, GA, Rybakowski, JK, Schalling, M, Schofield, PR, Schubert, KO, Schulte, EC, Schweizer, BW, Severino, G, Shekhtman, T, Shilling, PD, Shimoda, K, Simhandl, C, Mitchell, Philip ; https://orcid.org/0000-0002-7954-5235, 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 ; https://orcid.org/0000-0003-4014-4490, 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 ; https://orcid.org/0000-0002-1966-5120, Rouleau, GA, Rybakowski, JK, Schalling, M, Schofield, PR, Schubert, KO, Schulte, EC, Schweizer, BW, Severino, G, Shekhtman, T, Shilling, PD, Shimoda, K, Simhandl, C, and Mitchell, Philip ; https://orcid.org/0000-0002-7954-5235

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, hyperte

Published
2024

4. Immunogenetics of lithium response and psychiatric phenotypes in patients with bipolar disorder

Author

Herrera-Rivero, M, Gutiérrez-Fragoso, K, Kurtz, J, Baune, BT, Thalamuthu, A ; https://orcid.org/0000-0002-7114-1260, Amare, AT, Adli, M, Akiyama, K, Akula, N, 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 ; https://orcid.org/0000-0003-4014-4490, 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 ; https://orcid.org/0000-0002-1966-5120, Rouleau, GA, Rybakowski, JK, Schalling, M, Schofield, PR ; https://orcid.org/0000-0003-2967-9662, Schubert, KO, Schulte, EC, Schweizer, BW, Severino, G, Mitchell, Philip ; https://orcid.org/0000-0002-7954-5235, Herrera-Rivero, M, Gutiérrez-Fragoso, K, Kurtz, J, Baune, BT, Thalamuthu, A ; https://orcid.org/0000-0002-7114-1260, Amare, AT, Adli, M, Akiyama, K, Akula, N, 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 ; https://orcid.org/0000-0003-4014-4490, 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 ; https://orcid.org/0000-0002-1966-5120, Rouleau, GA, Rybakowski, JK, Schalling, M, Schofield, PR ; https://orcid.org/0000-0003-2967-9662, Schubert, KO, Schulte, EC, Schweizer, BW, Severino, G, and Mitchell, Philip ; https://orcid.org/0000-0002-7954-5235

Published
2024

10. Anxiety, mood, and substance use disorders in adult men and women with and without attention-deficit/hyperactivity disorder: A substantive and methodological overview.

Author

Hartman, C.A., Larsson, H., Vos, M de, Bellato, A., Libutzki, B., Solberg, B.S., Chen, Q., Rietz, E. Du, Mostert, J.C., Kittel-Schneider, S., Cormand, B., Ribasés, M., Klungsøyr, K., Haavik, J., Dalsgaard, S., Cortese, S., Faraone, S.V, Reif, A., Hartman, C.A., Larsson, H., Vos, M de, Bellato, A., Libutzki, B., Solberg, B.S., Chen, Q., Rietz, E. Du, Mostert, J.C., Kittel-Schneider, S., Cormand, B., Ribasés, M., Klungsøyr, K., Haavik, J., Dalsgaard, S., Cortese, S., Faraone, S.V, and Reif, A.

Abstract

01 augustus 2023, Item does not contain fulltext, Knowledge on psychiatric comorbidity in adult ADHD is essential for prevention, detection, and treatment of these conditions. This review (1) focuses on large studies (n > 10,000; surveys, claims data, population registries) to identify (a) overall, (b) sex- and (c) age-specific patterns of comorbidity of anxiety disorders (ADs), major depressive disorder (MDD), bipolar disorder (BD) and substance use disorders (SUDs) in adults with ADHD relative to adults without ADHD; and (2) describes methodological challenges relating to establishing comorbidity in ADHD in adults as well as priorities for future research. Meta-analyses (ADHD: n = 550,748; no ADHD n = 14,546,814) yielded pooled odds ratios of 5.0(CI:3.29-7.46) for ADs, 4.5(CI:2.44-8.34) for MDD, 8.7(CI:5.47-13.89) for BD and 4.6(CI:2.72-7.80) for SUDs, indicating strong differences in adults with compared to adults without ADHD. Moderation by sex was not found: high comorbidity held for both men and women with sex-specific patterns as in the general population: higher prevalences of ADs, MDD and BD in women and a higher prevalence of SUDs in men. Insufficient data on different phases of the adult lifespan prevented conclusions on developmental changes in comorbidity. We discuss methodological challenges, knowledge gaps, and future research priorities.

Published
2023

15. The genetic contribution of the NO system at the glutamatergic post-synapse to schizophrenia: Further evidence and meta-analysis

Author

Weber, H., Klamer, D., Freudenberg, F., Kittel-Schneider, S., Rivero, O., Scholz, C.-J., Volkert, J., Kopf, J., Heupel, J., Herterich, S., Adolfsson, R., Alttoa, A., Post, A., Grußendorf, H., Kramer, A., Gessner, A., Schmidt, B., Hempel, S., Jacob, C.P., Sanjuán, J., Moltó, M.D., Lesch, K.-P., Freitag, C.M., Kent, L., and Reif, A.

Published
2014
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23. Non-mental diseases associated with ADHD across the lifespan: Fidgety Philipp and Pippi Longstocking at risk of multimorbidity?

Author

Kittel-Schneider, S., Arteaga-Henriquez, G., Arias Vasquez, A., Asherson, P., Banaschewski, T., Brikell, I., Buitelaar, J.K., Cormand, B., Faraone, S.V, Freitag, C.M., Ginsberg, Y., Haavik, J., Hartman, Catharina A., Kuntsi, J., Larsson, H., Matura, S., McNeill, R.V., Ramos-Quiroga, J.A., Ribases, M., Romanos, M., Vainieri, I., Franke, B., Reif, A., Kittel-Schneider, S., Arteaga-Henriquez, G., Arias Vasquez, A., Asherson, P., Banaschewski, T., Brikell, I., Buitelaar, J.K., Cormand, B., Faraone, S.V, Freitag, C.M., Ginsberg, Y., Haavik, J., Hartman, Catharina A., Kuntsi, J., Larsson, H., Matura, S., McNeill, R.V., Ramos-Quiroga, J.A., Ribases, M., Romanos, M., Vainieri, I., Franke, B., and Reif, A.

Abstract

Item does not contain fulltext, Several non-mental diseases seem to be associated with an increased risk of ADHD and ADHD seems to be associated with increased risk for non-mental diseases. The underlying trajectories leading to such brain-body co-occurrences are often unclear - are there direct causal relationships from one disorder to the other, or does the sharing of genetic and/or environmental risk factors lead to their occurring together more frequently or both? Our goal with this narrative review was to provide a conceptual synthesis of the associations between ADHD and non-mental disease across the lifespan. We discuss potential shared pathologic mechanisms, genetic background and treatments in co-occurring diseases. For those co-occurrences for which published studies with sufficient sample sizes exist, meta-analyses have been published by others and we discuss those in detail. We conclude that non-mental diseases are common in ADHD and vice versa and add to the disease burden of the patient across the lifespan. Insufficient attention to such co-occurring conditions may result in missed diagnoses and suboptimal treatment in the affected individuals.

Published
2022

24. 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

27. Non-mental diseases associated with ADHD across the lifespan: Fidgety Philipp and Pippi Longstocking at risk of multimorbidity?

Author

Kittel-Schneider S, Arteaga-Henriquez G, Vasquez AA, Asherson P, Banaschewski T, Brikell I, Buitelaar J, Cormand B, Faraone SV, Freitag CM, Ginsberg Y, Haavik J, Hartman CA, Kuntsi J, Larsson H, Matura S, McNeill RV, Antoni Ramos-Quiroga J, Ribases M, Romanos M, Vainieri I, Franke B, and Reif A

Subjects
Epilepsy, Elimination disorders, Diabetes mellitus type II, Attention-deficit, hyperactivity disorder, Obesity, Somatic disorders, Non-mental disease, Asthma, Migraine
Abstract

Several non-mental diseases seem to be associated with an increased risk of ADHD and ADHD seems to be associated with increased risk for non-mental diseases. The underlying trajectories leading to such brain-body co occurrences are often unclear are there direct causal relationships from one disorder to the other, or does the sharing of genetic and/or environmental risk factors lead to their occurring together more frequently or both? Our goal with this narrative review was to provide a conceptual synthesis of the associations between ADHD and non-mental disease across the lifespan. We discuss potential shared pathologic mechanisms, genetic background and treatments in co-occurring diseases. For those co-occurrences for which published studies with sufficient sample sizes exist, meta-analyses have been published by others and we discuss those in detail. We conclude that non-mental diseases are common in ADHD and vice versa and add to the disease burden of the patient across the lifespan. Insufficient attention to such co-occurring conditions may result in missed diagnoses and suboptimal treatment in the affected individuals.

Published
2022

30. Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology

Author

Mullins, N. Forstner, A.J. O’Connell, K.S. Coombes, B. Coleman, J.R.I. Qiao, Z. Als, T.D. Bigdeli, T.B. Børte, S. Bryois, J. Charney, A.W. Drange, O.K. Gandal, M.J. Hagenaars, S.P. Ikeda, M. Kamitaki, N. Kim, M. Krebs, K. Panagiotaropoulou, G. Schilder, B.M. Sloofman, L.G. Steinberg, S. Trubetskoy, V. Winsvold, B.S. Won, H.-H. Abramova, L. Adorjan, K. Agerbo, E. Al Eissa, M. Albani, D. Alliey-Rodriguez, N. Anjorin, A. Antilla, V. Antoniou, A. Awasthi, S. Baek, J.H. Bækvad-Hansen, M. Bass, N. Bauer, M. Beins, E.C. Bergen, S.E. Birner, A. Bøcker Pedersen, C. Bøen, E. Boks, M.P. Bosch, R. Brum, M. Brumpton, B.M. Brunkhorst-Kanaan, N. Budde, M. Bybjerg-Grauholm, J. Byerley, W. Cairns, M. Casas, M. Cervantes, P. Clarke, T.-K. Cruceanu, C. Cuellar-Barboza, A. Cunningham, J. Curtis, D. Czerski, P.M. Dale, A.M. Dalkner, N. David, F.S. Degenhardt, F. Djurovic, S. Dobbyn, A.L. Douzenis, A. Elvsåshagen, T. Escott-Price, V. Ferrier, I.N. Fiorentino, A. Foroud, T.M. Forty, L. Frank, J. Frei, O. Freimer, N.B. Frisén, L. Gade, K. Garnham, J. Gelernter, J. Giørtz Pedersen, M. Gizer, I.R. Gordon, S.D. Gordon-Smith, K. Greenwood, T.A. Grove, J. Guzman-Parra, J. Ha, K. Haraldsson, M. Hautzinger, M. Heilbronner, U. Hellgren, D. Herms, S. Hoffmann, P. Holmans, P.A. Huckins, L. Jamain, S. Johnson, J.S. Kalman, J.L. Kamatani, Y. Kennedy, J.L. Kittel-Schneider, S. Knowles, J.A. Kogevinas, M. Koromina, M. Kranz, T.M. Kranzler, H.R. Kubo, M. Kupka, R. Kushner, S.A. Lavebratt, C. Lawrence, J. Leber, M. Lee, H.-J. Lee, P.H. Levy, S.E. Lewis, C. Liao, C. Lucae, S. Lundberg, M. MacIntyre, D.J. Magnusson, S.H. Maier, W. Maihofer, A. Malaspina, D. Maratou, E. Martinsson, L. Mattheisen, M. McCarroll, S.A. McGregor, N.W. McGuffin, P. McKay, J.D. Medeiros, H. Medland, S.E. Millischer, V. Montgomery, G.W. Moran, J.L. Morris, D.W. Mühleisen, T.W. O’Brien, N. O’Donovan, C. Olde Loohuis, L.M. Oruc, L. Papiol, S. Pardiñas, A.F. Perry, A. Pfennig, A. Porichi, E. Potash, J.B. Quested, D. Raj, T. Rapaport, M.H. DePaulo, J.R. Regeer, E.J. Rice, J.P. Rivas, F. Rivera, M. Roth, J. Roussos, P. Ruderfer, D.M. Sánchez-Mora, C. Schulte, E.C. Senner, F. Sharp, S. Shilling, P.D. Sigurdsson, E. Sirignano, L. Slaney, C. Smeland, O.B. Smith, D.J. Sobell, J.L. Søholm Hansen, C. Soler Artigas, M. Spijker, A.T. Stein, D.J. Strauss, J.S. Świątkowska, B. Terao, C. Thorgeirsson, T.E. Toma, C. Tooney, P. Tsermpini, E.-E. Vawter, M.P. Vedder, H. Walters, J.T.R. Witt, S.H. Xi, S. Xu, W. Yang, J.M.K. Young, A.H. Young, H. Zandi, P.P. Zhou, H. Zillich, L. Adolfsson, R. Agartz, I. Alda, M. Alfredsson, L. Babadjanova, G. Backlund, L. Baune, B.T. Bellivier, F. Bengesser, S. Berrettini, W.H. Blackwood, D.H.R. Boehnke, M. Børglum, A.D. Breen, G. Carr, V.J. Catts, S. Corvin, A. Craddock, N. Dannlowski, U. Dikeos, D. Esko, T. Etain, B. Ferentinos, P. Frye, M. Fullerton, J.M. Gawlik, M. Gershon, E.S. Goes, F.S. Green, M.J. Grigoroiu-Serbanescu, M. Hauser, J. Henskens, F. Hillert, J. Hong, K.S. Hougaard, D.M. Hultman, C.M. Hveem, K. Iwata, N. Jablensky, A.V. Jones, I. Jones, L.A. Kahn, R.S. Kelsoe, J.R. Kirov, G. Landén, M. Leboyer, M. Lewis, C.M. Li, Q.S. Lissowska, J. Lochner, C. Loughland, C. Martin, N.G. Mathews, C.A. Mayoral, F. McElroy, S.L. McIntosh, A.M. McMahon, F.J. Melle, I. Michie, P. Milani, L. Mitchell, P.B. Morken, G. Mors, O. Mortensen, P.B. Mowry, B. Müller-Myhsok, B. Myers, R.M. Neale, B.M. Nievergelt, C.M. Nordentoft, M. Nöthen, M.M. O’Donovan, M.C. Oedegaard, K.J. Olsson, T. Owen, M.J. Paciga, S.A. Pantelis, C. Pato, C. Pato, M.T. Patrinos, G.P. Perlis, R.H. Posthuma, D. Ramos-Quiroga, J.A. Reif, A. Reininghaus, E.Z. Ribasés, M. Rietschel, M. Ripke, S. Rouleau, G.A. Saito, T. Schall, U. Schalling, M. Schofield, P.R. Schulze, T.G. Scott, L.J. Scott, R.J. Serretti, A. Shannon Weickert, C. Smoller, J.W. Stefansson, H. Stefansson, K. Stordal, E. Streit, F. Sullivan, P.F. Turecki, G. Vaaler, A.E. Vieta, E. Vincent, J.B. Waldman, I.D. Weickert, T.W. Werge, T. Wray, N.R. Zwart, J.-A. Biernacka, J.M. Nurnberger, J.I. Cichon, S. Edenberg, H.J. Stahl, E.A. McQuillin, A. Di Florio, A. Ophoff, R.A. Andreassen, O.A. HUNT All-In Psychiatry

Abstract

Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies. © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.

Published
2021

31. Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology

Author

Mullins, N. Forstner, A.J. O’Connell, K.S. Coombes, B. Coleman, J.R.I. Qiao, Z. Als, T.D. Bigdeli, T.B. Børte, S. Bryois, J. Charney, A.W. Drange, O.K. Gandal, M.J. Hagenaars, S.P. Ikeda, M. Kamitaki, N. Kim, M. Krebs, K. Panagiotaropoulou, G. Schilder, B.M. Sloofman, L.G. Steinberg, S. Trubetskoy, V. Winsvold, B.S. Won, H.-H. Abramova, L. Adorjan, K. Agerbo, E. Al Eissa, M. Albani, D. Alliey-Rodriguez, N. Anjorin, A. Antilla, V. Antoniou, A. Awasthi, S. Baek, J.H. Bækvad-Hansen, M. Bass, N. Bauer, M. Beins, E.C. Bergen, S.E. Birner, A. Bøcker Pedersen, C. Bøen, E. Boks, M.P. Bosch, R. Brum, M. Brumpton, B.M. Brunkhorst-Kanaan, N. Budde, M. Bybjerg-Grauholm, J. Byerley, W. Cairns, M. Casas, M. Cervantes, P. Clarke, T.-K. Cruceanu, C. Cuellar-Barboza, A. Cunningham, J. Curtis, D. Czerski, P.M. Dale, A.M. Dalkner, N. David, F.S. Degenhardt, F. Djurovic, S. Dobbyn, A.L. Douzenis, A. Elvsåshagen, T. Escott-Price, V. Ferrier, I.N. Fiorentino, A. Foroud, T.M. Forty, L. Frank, J. Frei, O. Freimer, N.B. Frisén, L. Gade, K. Garnham, J. Gelernter, J. Giørtz Pedersen, M. Gizer, I.R. Gordon, S.D. Gordon-Smith, K. Greenwood, T.A. Grove, J. Guzman-Parra, J. Ha, K. Haraldsson, M. Hautzinger, M. Heilbronner, U. Hellgren, D. Herms, S. Hoffmann, P. Holmans, P.A. Huckins, L. Jamain, S. Johnson, J.S. Kalman, J.L. Kamatani, Y. Kennedy, J.L. Kittel-Schneider, S. Knowles, J.A. Kogevinas, M. Koromina, M. Kranz, T.M. Kranzler, H.R. Kubo, M. Kupka, R. Kushner, S.A. Lavebratt, C. Lawrence, J. Leber, M. Lee, H.-J. Lee, P.H. Levy, S.E. Lewis, C. Liao, C. Lucae, S. Lundberg, M. MacIntyre, D.J. Magnusson, S.H. Maier, W. Maihofer, A. Malaspina, D. Maratou, E. Martinsson, L. Mattheisen, M. McCarroll, S.A. McGregor, N.W. McGuffin, P. McKay, J.D. Medeiros, H. Medland, S.E. Millischer, V. Montgomery, G.W. Moran, J.L. Morris, D.W. Mühleisen, T.W. O’Brien, N. O’Donovan, C. Olde Loohuis, L.M. Oruc, L. Papiol, S. Pardiñas, A.F. Perry, A. Pfennig, A. Porichi, E. Potash, J.B. Quested, D. Raj, T. Rapaport, M and Mullins, N. Forstner, A.J. O’Connell, K.S. Coombes, B. Coleman, J.R.I. Qiao, Z. Als, T.D. Bigdeli, T.B. Børte, S. Bryois, J. Charney, A.W. Drange, O.K. Gandal, M.J. Hagenaars, S.P. Ikeda, M. Kamitaki, N. Kim, M. Krebs, K. Panagiotaropoulou, G. Schilder, B.M. Sloofman, L.G. Steinberg, S. Trubetskoy, V. Winsvold, B.S. Won, H.-H. Abramova, L. Adorjan, K. Agerbo, E. Al Eissa, M. Albani, D. Alliey-Rodriguez, N. Anjorin, A. Antilla, V. Antoniou, A. Awasthi, S. Baek, J.H. Bækvad-Hansen, M. Bass, N. Bauer, M. Beins, E.C. Bergen, S.E. Birner, A. Bøcker Pedersen, C. Bøen, E. Boks, M.P. Bosch, R. Brum, M. Brumpton, B.M. Brunkhorst-Kanaan, N. Budde, M. Bybjerg-Grauholm, J. Byerley, W. Cairns, M. Casas, M. Cervantes, P. Clarke, T.-K. Cruceanu, C. Cuellar-Barboza, A. Cunningham, J. Curtis, D. Czerski, P.M. Dale, A.M. Dalkner, N. David, F.S. Degenhardt, F. Djurovic, S. Dobbyn, A.L. Douzenis, A. Elvsåshagen, T. Escott-Price, V. Ferrier, I.N. Fiorentino, A. Foroud, T.M. Forty, L. Frank, J. Frei, O. Freimer, N.B. Frisén, L. Gade, K. Garnham, J. Gelernter, J. Giørtz Pedersen, M. Gizer, I.R. Gordon, S.D. Gordon-Smith, K. Greenwood, T.A. Grove, J. Guzman-Parra, J. Ha, K. Haraldsson, M. Hautzinger, M. Heilbronner, U. Hellgren, D. Herms, S. Hoffmann, P. Holmans, P.A. Huckins, L. Jamain, S. Johnson, J.S. Kalman, J.L. Kamatani, Y. Kennedy, J.L. Kittel-Schneider, S. Knowles, J.A. Kogevinas, M. Koromina, M. Kranz, T.M. Kranzler, H.R. Kubo, M. Kupka, R. Kushner, S.A. Lavebratt, C. Lawrence, J. Leber, M. Lee, H.-J. Lee, P.H. Levy, S.E. Lewis, C. Liao, C. Lucae, S. Lundberg, M. MacIntyre, D.J. Magnusson, S.H. Maier, W. Maihofer, A. Malaspina, D. Maratou, E. Martinsson, L. Mattheisen, M. McCarroll, S.A. McGregor, N.W. McGuffin, P. McKay, J.D. Medeiros, H. Medland, S.E. Millischer, V. Montgomery, G.W. Moran, J.L. Morris, D.W. Mühleisen, T.W. O’Brien, N. O’Donovan, C. Olde Loohuis, L.M. Oruc, L. Papiol, S. Pardiñas, A.F. Perry, A. Pfennig, A. Porichi, E. Potash, J.B. Quested, D. Raj, T. Rapaport, M

Abstract

Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies. © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.

Published
2021

32. 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 ; https://orcid.org/0000-0003-4014-4490, 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, Mitchell, Philip ; https://orcid.org/0000-0002-7954-5235, 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 ; https://orcid.org/0000-0003-4014-4490, 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, and Mitchell, Philip ; https://orcid.org/0000-0002-7954-5235

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

33. Prediction of lithium response using genomic data

Author

Stone, W, Nunes, A, Akiyama, K, Akula, N, Ardau, R, Aubry, JM, Backlund, L, Bauer, M, Bellivier, F, Cervantes, P, Chen, HC, Chillotti, C, Cruceanu, C, Dayer, A, Degenhardt, F, Del Zompo, M, Forstner, AJ, Frye, M, Fullerton, JM ; https://orcid.org/0000-0003-4014-4490, Grigoroiu-Serbanescu, M, Grof, P, Hashimoto, R, Hou, L, Jiménez, E, Kato, T, Kelsoe, J, Kittel-Schneider, S, Kuo, PH, Kusumi, I, Lavebratt, C, Manchia, M, Martinsson, L, Mattheisen, M, McMahon, FJ, Millischer, V, Mitchell, PB ; https://orcid.org/0000-0002-7954-5235, Nöthen, MM, O’Donovan, C, Ozaki, N, Pisanu, C, Reif, A, Rietschel, M, Rouleau, G, Rybakowski, J, Schalling, M, Schofield, PR, Schulze, TG, Severino, G, Squassina, A, Veeh, J, Vieta, E, Trappenberg, T, Alda, M, Stone, W, Nunes, A, Akiyama, K, Akula, N, Ardau, R, Aubry, JM, Backlund, L, Bauer, M, Bellivier, F, Cervantes, P, Chen, HC, Chillotti, C, Cruceanu, C, Dayer, A, Degenhardt, F, Del Zompo, M, Forstner, AJ, Frye, M, Fullerton, JM ; https://orcid.org/0000-0003-4014-4490, Grigoroiu-Serbanescu, M, Grof, P, Hashimoto, R, Hou, L, Jiménez, E, Kato, T, Kelsoe, J, Kittel-Schneider, S, Kuo, PH, Kusumi, I, Lavebratt, C, Manchia, M, Martinsson, L, Mattheisen, M, McMahon, FJ, Millischer, V, Mitchell, PB ; https://orcid.org/0000-0002-7954-5235, Nöthen, MM, O’Donovan, C, Ozaki, N, Pisanu, C, Reif, A, Rietschel, M, Rouleau, G, Rybakowski, J, Schalling, M, Schofield, PR, Schulze, TG, Severino, G, Squassina, A, Veeh, J, Vieta, E, Trappenberg, T, and Alda, M

Abstract

Predicting lithium response prior to treatment could both expedite therapy and avoid exposure to side effects. Since lithium responsiveness may be heritable, its predictability based on genomic data is of interest. We thus evaluate the degree to which lithium response can be predicted with a machine learning (ML) approach using genomic data. Using the largest existing genomic dataset in the lithium response literature (n = 2210 across 14 international sites; 29% responders), we evaluated the degree to which lithium response could be predicted based on 47,465 genotyped single nucleotide polymorphisms using a supervised ML approach. Under appropriate cross-validation procedures, lithium response could be predicted to above-chance levels in two constituent sites (Halifax, Cohen’s kappa 0.15, 95% confidence interval, CI [0.07, 0.24]; and Würzburg, kappa 0.2 [0.1, 0.3]). Variants with shared importance in these models showed over-representation of postsynaptic membrane related genes. Lithium response was not predictable in the pooled dataset (kappa 0.02 [− 0.01, 0.04]), although non-trivial performance was achieved within a restricted dataset including only those patients followed prospectively (kappa 0.09 [0.04, 0.14]). Genomic classification of lithium response remains a promising but difficult task. Classification performance could potentially be improved by further harmonization of data collection procedures.

Published
2021

34. Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology

Author

Mullins, N, Forstner, AJ, O'Connell, KS, Coombes, B, Coleman, JR, Qiao, Z, Als, TD, Bigdeli, TB, Borte, S, Bryois, J, Charney, AW, Drange, OK, Gandal, MJ, Hagenaars, SP, Ikeda, M, Kamitaki, N, Kim, M, Krebs, K, Panagiotaropoulou, G, Schilder, BM, Sloofman, LG, Steinberg, S, Trubetskoy, V, Winsvold, BS, Won, H-H, Abramova, L, Adorjan, K, Agerbo, E, Al Eissa, M, Albani, D, Alliey-Rodriguez, N, Anjorin, A, Antilla, V, Antoniou, A, Awasthi, S, Baek, JH, Baekvad-Hansen, M, Bass, N, Bauer, M, Beins, EC, Bergen, SE, Birner, A, Pedersen, CB, Boen, E, Boks, MP, Bosch, R, Brum, M, Brumpton, BM, Brunkhorst-Kanaan, N, Budde, M, Bybjerg-Grauholm, J, Byerley, W, Cairns, M, Casas, M, Cervantes, P, Clarke, T-K, Cruceanu, C, Cuellar-Barboza, A, Cunningham, J, Curtis, D, Czerski, PM, Dale, AM, Dalkner, N, David, FS, Degenhardt, F, Djurovic, S, Dobbyn, AL, Douzenis, A, Elvsashagen, T, Escott-Price, V, Ferrier, IN, Fiorentino, A, Foroud, TM, Forty, L, Frank, J, Frei, O, Freimer, NB, Frisen, L, Gade, K, Garnham, J, Gelernter, J, Pedersen, MG, Gizer, IR, Gordon, SD, Gordon-Smith, K, Greenwood, TA, Grove, J, Guzman-Parra, J, Ha, K, Haraldsson, M, Hautzinger, M, Heilbronner, U, Hellgren, D, Herms, S, Hoffmann, P, Holmans, PA, Huckins, L, Jamain, S, Johnson, JS, Kalman, JL, Kamatani, Y, Kennedy, JL, Kittel-Schneider, S, Knowles, JA, Kogevinas, M, Koromina, M, Kranz, TM, Kranzler, HR, Kubo, M, Kupka, R, Kushner, SA, Lavebratt, C, Lawrence, J, Leber, M, Lee, H-J, Lee, PH, Levy, SE, Lewis, C, Liao, C, Lucae, S, Lundberg, M, MacIntyre, DJ, Maier, W, Maihofer, A, Malaspina, D, Maratou, E, Martinsson, L, Mattheisen, M, McCarroll, SA, McGregor, NW, McGuffin, P, McKay, JD, Medeiros, H, Medland, SE, Millischer, V, Montgomery, GW, Moran, JL, Morris, DW, Muhleisen, TW, O'Brien, N, O'Donovan, C, Loohuis, LMO, Oruc, L, Papiol, S, Pardinas, AF, Perry, A, Pfennig, A, Porichi, E, Potash, JB, Quested, D, Raj, T, Rapaport, MH, DePaulo, JR, Regeer, EJ, Rice, JP, Rivas, F, Rivera, M, Roth, J, Roussos, P, Ruderfer, DM, Sanchez-Mora, C, Schulte, EC, Senner, F, Sharp, S, Shilling, PD, Sigurdsson, E, Sirignano, L, Slaney, C, Smeland, OB, Sobell, JL, Hansen, CS, Artigas, MS, Spijker, AT, Stein, DJ, Strauss, JS, Swiatkowska, B, Terao, C, Thorgeirsson, TE, Toma, C, Tooney, P, Tsermpini, E-E, Vawter, MP, Vedder, H, Walters, JTR, Witt, SH, Xi, S, Xu, W, Yang, JMK, Young, AH, Young, H, Zandi, PP, Zhou, H, Zillich, L, Adolfsson, R, Agartz, I, Alda, M, Alfredsson, L, Babadjanova, G, Backlund, L, Baune, BT, Bellivier, F, Bengesser, S, Berrettini, WH, Blackwood, DHR, Boehnke, M, Borglum, AD, Breen, G, Carr, VJ, Catts, S, Corvin, A, Craddock, N, Dannlowski, U, Dikeos, D, Esko, T, Etain, B, Ferentinos, P, Frye, M, Fullerton, JM, Gawlik, M, Gershon, ES, Goes, F, Green, MJ, Grigoroiu-Serbanescu, M, Hauser, J, Henskens, F, Hillert, J, Hong, KS, Hougaard, DM, Hultman, CM, Hveem, K, Iwata, N, Jablensky, A, Jones, I, Jones, LA, Kahn, RS, Kelsoe, JR, Kirov, G, Landen, M, Leboyer, M, Lewis, CM, Li, QS, Lissowska, J, Lochner, C, Loughland, C, Martin, NG, Mathews, CA, Mayoral, F, McElroy, SL, McIntosh, AM, McMahon, FJ, Melle, I, Michie, P, Milani, L, Mitchell, PB, Morken, G, Mors, O, Mortensen, PB, Mowry, B, Muller-Myhsok, B, Myers, RM, Neale, BM, Nievergelt, CM, Nordentoft, M, Nothen, MM, ODonovan, MC, Oedegaard, KJ, Olsson, T, Owen, MJ, Paciga, SA, Pantelis, C, Pato, C, Pato, MT, Patrinos, GP, Perlis, RH, Posthuma, D, Ramos-Quiroga, JA, Reif, A, Reininghaus, EZ, Ribases, M, Rietschel, M, Ripke, S, Rouleau, GA, Saito, T, Schall, U, Schalling, M, Schofield, PR, Schulze, TG, Scott, LJ, Scott, RJ, Serretti, A, Weickert, CS, Smoller, JW, Stefansson, H, Stefansson, K, Stordal, E, Streit, F, Sullivan, PF, Turecki, G, Vaaler, AE, Vieta, E, Vincent, JB, Waldman, ID, Weickert, TW, Werge, T, Wray, NR, Zwart, J, Biernacka, JM, Nurnberger, J, Cichon, S, Edenberg, HJ, Stahl, EA, McQuillin, A, Di Florio, A, Ophoff, RA, Andreassen, OA, Mullins, N, Forstner, AJ, O'Connell, KS, Coombes, B, Coleman, JR, Qiao, Z, Als, TD, Bigdeli, TB, Borte, S, Bryois, J, Charney, AW, Drange, OK, Gandal, MJ, Hagenaars, SP, Ikeda, M, Kamitaki, N, Kim, M, Krebs, K, Panagiotaropoulou, G, Schilder, BM, Sloofman, LG, Steinberg, S, Trubetskoy, V, Winsvold, BS, Won, H-H, Abramova, L, Adorjan, K, Agerbo, E, Al Eissa, M, Albani, D, Alliey-Rodriguez, N, Anjorin, A, Antilla, V, Antoniou, A, Awasthi, S, Baek, JH, Baekvad-Hansen, M, Bass, N, Bauer, M, Beins, EC, Bergen, SE, Birner, A, Pedersen, CB, Boen, E, Boks, MP, Bosch, R, Brum, M, Brumpton, BM, Brunkhorst-Kanaan, N, Budde, M, Bybjerg-Grauholm, J, Byerley, W, Cairns, M, Casas, M, Cervantes, P, Clarke, T-K, Cruceanu, C, Cuellar-Barboza, A, Cunningham, J, Curtis, D, Czerski, PM, Dale, AM, Dalkner, N, David, FS, Degenhardt, F, Djurovic, S, Dobbyn, AL, Douzenis, A, Elvsashagen, T, Escott-Price, V, Ferrier, IN, Fiorentino, A, Foroud, TM, Forty, L, Frank, J, Frei, O, Freimer, NB, Frisen, L, Gade, K, Garnham, J, Gelernter, J, Pedersen, MG, Gizer, IR, Gordon, SD, Gordon-Smith, K, Greenwood, TA, Grove, J, Guzman-Parra, J, Ha, K, Haraldsson, M, Hautzinger, M, Heilbronner, U, Hellgren, D, Herms, S, Hoffmann, P, Holmans, PA, Huckins, L, Jamain, S, Johnson, JS, Kalman, JL, Kamatani, Y, Kennedy, JL, Kittel-Schneider, S, Knowles, JA, Kogevinas, M, Koromina, M, Kranz, TM, Kranzler, HR, Kubo, M, Kupka, R, Kushner, SA, Lavebratt, C, Lawrence, J, Leber, M, Lee, H-J, Lee, PH, Levy, SE, Lewis, C, Liao, C, Lucae, S, Lundberg, M, MacIntyre, DJ, Maier, W, Maihofer, A, Malaspina, D, Maratou, E, Martinsson, L, Mattheisen, M, McCarroll, SA, McGregor, NW, McGuffin, P, McKay, JD, Medeiros, H, Medland, SE, Millischer, V, Montgomery, GW, Moran, JL, Morris, DW, Muhleisen, TW, O'Brien, N, O'Donovan, C, Loohuis, LMO, Oruc, L, Papiol, S, Pardinas, AF, Perry, A, Pfennig, A, Porichi, E, Potash, JB, Quested, D, Raj, T, Rapaport, MH, DePaulo, JR, Regeer, EJ, Rice, JP, Rivas, F, Rivera, M, Roth, J, Roussos, P, Ruderfer, DM, Sanchez-Mora, C, Schulte, EC, Senner, F, Sharp, S, Shilling, PD, Sigurdsson, E, Sirignano, L, Slaney, C, Smeland, OB, Sobell, JL, Hansen, CS, Artigas, MS, Spijker, AT, Stein, DJ, Strauss, JS, Swiatkowska, B, Terao, C, Thorgeirsson, TE, Toma, C, Tooney, P, Tsermpini, E-E, Vawter, MP, Vedder, H, Walters, JTR, Witt, SH, Xi, S, Xu, W, Yang, JMK, Young, AH, Young, H, Zandi, PP, Zhou, H, Zillich, L, Adolfsson, R, Agartz, I, Alda, M, Alfredsson, L, Babadjanova, G, Backlund, L, Baune, BT, Bellivier, F, Bengesser, S, Berrettini, WH, Blackwood, DHR, Boehnke, M, Borglum, AD, Breen, G, Carr, VJ, Catts, S, Corvin, A, Craddock, N, Dannlowski, U, Dikeos, D, Esko, T, Etain, B, Ferentinos, P, Frye, M, Fullerton, JM, Gawlik, M, Gershon, ES, Goes, F, Green, MJ, Grigoroiu-Serbanescu, M, Hauser, J, Henskens, F, Hillert, J, Hong, KS, Hougaard, DM, Hultman, CM, Hveem, K, Iwata, N, Jablensky, A, Jones, I, Jones, LA, Kahn, RS, Kelsoe, JR, Kirov, G, Landen, M, Leboyer, M, Lewis, CM, Li, QS, Lissowska, J, Lochner, C, Loughland, C, Martin, NG, Mathews, CA, Mayoral, F, McElroy, SL, McIntosh, AM, McMahon, FJ, Melle, I, Michie, P, Milani, L, Mitchell, PB, Morken, G, Mors, O, Mortensen, PB, Mowry, B, Muller-Myhsok, B, Myers, RM, Neale, BM, Nievergelt, CM, Nordentoft, M, Nothen, MM, ODonovan, MC, Oedegaard, KJ, Olsson, T, Owen, MJ, Paciga, SA, Pantelis, C, Pato, C, Pato, MT, Patrinos, GP, Perlis, RH, Posthuma, D, Ramos-Quiroga, JA, Reif, A, Reininghaus, EZ, Ribases, M, Rietschel, M, Ripke, S, Rouleau, GA, Saito, T, Schall, U, Schalling, M, Schofield, PR, Schulze, TG, Scott, LJ, Scott, RJ, Serretti, A, Weickert, CS, Smoller, JW, Stefansson, H, Stefansson, K, Stordal, E, Streit, F, Sullivan, PF, Turecki, G, Vaaler, AE, Vieta, E, Vincent, JB, Waldman, ID, Weickert, TW, Werge, T, Wray, NR, Zwart, J, Biernacka, JM, Nurnberger, J, Cichon, S, Edenberg, HJ, Stahl, EA, McQuillin, A, Di Florio, A, Ophoff, RA, and Andreassen, OA

Abstract

Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.

Published
2021

35. 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

36. 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

43. Shared genetic background between children and adults with attention deficit/hyperactivity disorder

Author

Rovira P, Demontis D, Sánchez-Mora C, Zayats T, Klein M, Mota NR, Weber H, Garcia-Martínez I, Pagerols M, Vilar L, Arribas L, Richarte V, Corrales M, Fadeuilhe C, Bosch R, Martin GE, Almos P, Doyle AE, Grevet EH, Grimm O, Halmøy A, Hoogman M, Hutz M, Jacob CP, Kittel-Schneider S, Knappskog PM, Lundervold AJ, Rivero O, Rovaris DL, Salatino-Oliveira A, da Silva BS, Svirin E, Sprooten E, Strekalova T, ADHD Working Group of the Psychiatric Genomics Consortium, 23andMe Research team, Arias-Vasquez A, Sonuga-Barke EJS, Asherson P, Bau CHD, Buitelaar JK, Cormand B, Faraone SV, Haavik J, Johansson SE, Kuntsi J, Larsson H, Lesch KP, Reif A, Rohde LA, Casas M, Børglum AD, Franke B, Ramos-Quiroga JA, Artigas MS, and Ribasés M

Subjects
mental disorders, behavioral disciplines and activities
Abstract

Attention deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder characterized by age-inappropriate symptoms of inattention, impulsivity, and hyperactivity that persist into adulthood in the majority of the diagnosed children. Despite several risk factors during childhood predicting the persistence of ADHD symptoms into adulthood, the genetic architecture underlying the trajectory of ADHD over time is still unclear. We set out to study the contribution of common genetic variants to the risk for ADHD across the lifespan by conducting meta-analyses of genome-wide association studies on persistent ADHD in adults and ADHD in childhood separately and jointly, and by comparing the genetic background between them in a total sample of 17,149 cases and 32,411 controls. Our results show nine new independent loci and support a shared contribution of common genetic variants to ADHD in children and adults. No subgroup heterogeneity was observed among children, while this group consists of future remitting and persistent individuals. We report similar patterns of genetic correlation of ADHD with other ADHD-related datasets and different traits and disorders among adults, children, and when combining both groups. These findings confirm that persistent ADHD in adults is a neurodevelopmental disorder and extend the existing hypothesis of a shared genetic architecture underlying ADHD and different traits to a lifespan perspective.

Published
2020

44. Shared genetic background between children and adults with attention deficit/hyperactivity disorder

Author

Rovira, P., Demontis, D., Sánchez-Mora, C., Zayats, T., Klein, M., Mota, N., Weber, H., Garcia-Martínez, I., Pagerols, M., Vilar-Ribó, L., Arribas, L., Richarte, V., Corrales, M., Fadeuilhe, C., Bosch, Rosa, Martin, G.E., Almos, P., Doyle, A.E., Grevet, E.H., Grimm, O., Halmøy, A., Hoogman, M., Hutz, M., Jacob, C.P., Kittel-Schneider, S., Knappskog, P.M., Lundervold, A.J., Rivero, O., Rovaris, D.L., Salatino-Oliveira, A., Silva, B.S. da, Svirin, E., Sprooten, E., Strekalova, T., Arias-Vasquez, A., Sonuga-Barke, E.J., Asherson, P., Bau, C.H.D., Buitelaar, J.K., Cormand, B., Faraone, S.V, Haavik, J., Johansson, S.E., Kuntsi, J., Larsson, H., Lesch, K.P., Reif, A., Rohde, L.A., Casas, M., Børglum, A.D., Franke, B., Ramos-Quiroga, J.A., Artigas, M. Soler, Ribasés, M., Rovira, P., Demontis, D., Sánchez-Mora, C., Zayats, T., Klein, M., Mota, N., Weber, H., Garcia-Martínez, I., Pagerols, M., Vilar-Ribó, L., Arribas, L., Richarte, V., Corrales, M., Fadeuilhe, C., Bosch, Rosa, Martin, G.E., Almos, P., Doyle, A.E., Grevet, E.H., Grimm, O., Halmøy, A., Hoogman, M., Hutz, M., Jacob, C.P., Kittel-Schneider, S., Knappskog, P.M., Lundervold, A.J., Rivero, O., Rovaris, D.L., Salatino-Oliveira, A., Silva, B.S. da, Svirin, E., Sprooten, E., Strekalova, T., Arias-Vasquez, A., Sonuga-Barke, E.J., Asherson, P., Bau, C.H.D., Buitelaar, J.K., Cormand, B., Faraone, S.V, Haavik, J., Johansson, S.E., Kuntsi, J., Larsson, H., Lesch, K.P., Reif, A., Rohde, L.A., Casas, M., Børglum, A.D., Franke, B., Ramos-Quiroga, J.A., Artigas, M. Soler, and Ribasés, M.

Abstract

Contains fulltext : 225384.pdf (Publisher’s version ) (Open Access), Attention deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder characterized by age-inappropriate symptoms of inattention, impulsivity, and hyperactivity that persist into adulthood in the majority of the diagnosed children. Despite several risk factors during childhood predicting the persistence of ADHD symptoms into adulthood, the genetic architecture underlying the trajectory of ADHD over time is still unclear. We set out to study the contribution of common genetic variants to the risk for ADHD across the lifespan by conducting meta-analyses of genome-wide association studies on persistent ADHD in adults and ADHD in childhood separately and jointly, and by comparing the genetic background between them in a total sample of 17,149 cases and 32,411 controls. Our results show nine new independent loci and support a shared contribution of common genetic variants to ADHD in children and adults. No subgroup heterogeneity was observed among children, while this group consists of future remitting and persistent individuals. We report similar patterns of genetic correlation of ADHD with other ADHD-related datasets and different traits and disorders among adults, children, and when combining both groups. These findings confirm that persistent ADHD in adults is a neurodevelopmental disorder and extend the existing hypothesis of a shared genetic architecture underlying ADHD and different traits to a lifespan perspective.

Published
2020

45. Improving early recognition and intervention in people at increased risk for the development of bipolar disorder: study protocol of a prospective-longitudinal, naturalistic cohort study (Early-BipoLife).

Author

Pfennig, A, Leopold, K, Martini, J, Boehme, A, Lambert, M, Stamm, T, Bermpohl, F, Reif, A, Kittel-Schneider, S, Juckel, G, Fallgatter, AJ, Kircher, T, Jansen, A, Pfeiffer, S, Berndt, C, Rottmann-Wolf, M, Sauer, C, Ritter, P, Correll, CU, Bechdolf, A, Falkenberg, I, Bauer, M, Pfennig, A, Leopold, K, Martini, J, Boehme, A, Lambert, M, Stamm, T, Bermpohl, F, Reif, A, Kittel-Schneider, S, Juckel, G, Fallgatter, AJ, Kircher, T, Jansen, A, Pfeiffer, S, Berndt, C, Rottmann-Wolf, M, Sauer, C, Ritter, P, Correll, CU, Bechdolf, A, Falkenberg, I, and Bauer, M

Abstract

BACKGROUND: Bipolar disorders (BD) belong to the most severe mental disorders, characterized by an early onset and recurrent, severe episodes or a chronic course with poor psychosocial functioning in a proportion of patients. Many patients with BD experience substantial symptomatology months or even years before full BD manifestation. Adequate diagnosis and treatment is often delayed, which is associated with a worse outcome. This study aims to prospectively evaluate and improve early recognition and intervention strategies for persons at-risk for BD. METHODS: Early-BipoLife is a prospective-longitudinal cohort study of 1419 participants (aged 15-35 years) with at least five waves of assessment over a period of at least 2 years (baseline, 6, 12, 18 and 24 months). A research consortium of ten university and teaching hospitals across Germany conducts this study. The following risk groups (RGs) were recruited: RG I: help-seeking youth and young adults consulting early recognition centres/facilities presenting ≥ 1 of the proposed risk factors for BD, RG II: in-/outpatients with unipolar depressive syndrome, and RG III: in-/outpatients with attention-deficit/hyperactivity disorder (ADHD). The reference cohort was selected from the German representative IMAGEN cohort. Over the study period, the natural course of risk and resilience factors, early symptoms of BD and changes of symptom severity (including conversion to manifest BD) are observed. Psychometric properties of recently developed, structured instruments on potential risk factors for conversion to BD and subsyndromal symptomatology (Bipolar Prodrome Symptom Scale, Bipolar at-risk criteria, EPIbipolar) and biomarkers that potentially improve prediction are investigated. Moreover, actual treatment recommendations are monitored in the participating specialized services and compared to recently postulated clinical categorization and treatment guidance in the field of early BD. DISCUSSION: Findings from this study wil

Published
2020

46. Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder

Author

Demontis, D, Walters, R, Martin, J, Mattheisen, M, Als, T, Agerbo, E, Baldursson, G, Belliveau, R, Bybjerg-Grauholm, J, Baekvad-Hansen, M, Cerrato, F, Chambert, K, Churchhouse, C, Dumont, A, Eriksson, N, Gandal, M, Goldstein, J, Grasby, K, Grove, J, Gudmundsson, O, Hansen, C, Hauberg, M, Hollegaard, M, Howrigan, D, Huang, H, Maller, J, Martin, A, Martin, N, Moran, J, Pallesen, J, Palmer, D, Pedersen, C, Pedersen, M, Poterba, T, Poulsen, J, Ripke, S, Robinson, E, Satterstrom, F, Stefansson, H, Stevens, C, Turley, P, Walters, G, Won, H, Wright, M, Andreassen, O, Asherson, P, Burton, C, Boomsma, D, Cormand, B, Dalsgaard, S, Franke, B, Gelernter, J, Geschwind, D, Hakonarson, H, Haavik, J, Kranzler, H, Kuntsi, J, Langley, K, Lesch, K, Middeldorp, C, Reif, A, Rohde, L, Roussos, P, Schachar, R, Sklar, P, Sonuga-Barke, E, Sullivan, P, Thapar, A, Tung, J, Waldman, I, Medland, S, Stefansson, K, Nordentoft, M, Hougaard, D, Werge, T, Mors, O, Mortensen, P, Daly, M, Faraone, S, Borglum, A, Neale, B, Albayrak, O, Anney, R, Arranz, M, Banaschewski, T, Bau, C, Biederman, J, Buitelaar, J, Casas, M, Charach, A, Crosbie, J, Dempfle, A, Doyle, A, Ebstein, R, Elia, J, Freitag, C, Focker, M, Gill, M, Grevet, E, Hawi, Z, Hebebrand, J, Herpertz-Dahlmann, B, Hervas, A, Hinney, A, Hohmann, S, Holmans, P, Hutz, M, Ickowitz, A, Johansson, S, Kent, L, Kittel-Schneider, S, Lambregts-Rommelse, N, Lehmkuhl, G, Loo, S, McGough, J, Meyer, J, Mick, E, Middletion, F, Miranda, A, Mota, N, Mulas, F, Mulligan, A, Nelson, F, Nguyen, T, Oades, R, O'Donovan, M, Owen, M, Palmason, H, Ramos-Quiroga, J, Renner, T, Ribases, M, Rietschel, M, Rivero, O, Romanos, J, Romanos, M, Rothenberger, A, Royers, H, Sanchez-Mora, C, Scherag, A, Schimmelmann, B, Schafer, H, Sergeant, J, Sinzig, J, Smalley, S, Steinhausen, H, Thompson, M, Todorov, A, Vasquez, A, Walitza, S, Wang, Y, Warnke, A, Williams, N, Witt, S, Yang, L, Zayats, T, Zhang-James, Y, Smith, G, Davies, G, Ehli, E, Evans, D, Fedko, I, Greven, C, Groen-Blokhuis, M, Guxens, M, Hammerschlag, A, Hartman, C, Heinrich, J, Hottenga, J, Hudziak, J, Jugessur, A, Kemp, J, Krapohl, E, Murcia, M, Myhre, R, Nolte, I, Nyholt, D, Ormel, J, Ouwens, K, Pappa, I, Pennell, C, Plomin, R, Ring, S, Standl, M, Stergiakouli, E, St Pourcain, B, Stoltenberg, C, Sunyer, J, Thiering, E, Tiemeier, H, Tiesler, C, Timpson, N, Trzaskowski, M, van der Most, P, Vilor-Tejedor, N, Wang, C, Whitehouse, A, Zhao, H, Agee, M, Alipanahi, B, Auton, A, Bell, R, Bryc, K, Elson, S, Fontanillas, P, Furlotte, N, Hinds, D, Hromatka, B, Huber, K, Kleinman, A, Litterman, N, McIntyre, M, Mountain, J, Northover, C, Pitts, S, Sathirapongsasuti, J, Sazonova, O, Shelton, J, Shringarpure, S, Tian, C, Vacic, V, Wilson, C, ADHD Working Grp Psychiat Genomics, Early Lifecourse Genetic, 23andMe Res Team, Institute for Molecular Medicine Finland, Centre of Excellence in Complex Disease Genetics, Psychiatrie & Neuropsychologie, RS: MHeNs - R3 - Neuroscience, Psychiatry, ADHD Working Group of the Psychiatric Genomics Consortium (PGC), 23andme Research Team, University of St Andrews. Cellular Medicine Division, University of St Andrews. Institute of Behavioural and Neural Sciences, University of St Andrews. School of Medicine, Child and Adolescent Psychiatry / Psychology, Erasmus MC other, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Clinical Neuropsychology, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Personalized Medicine, Clinical Child and Family Studies, LEARN! - Child rearing, and APH - Methodology

Subjects
Netherlands Twin Register (NTR), Male, Trastorns per dèficit d'atenció amb hiperactivitat en els infants, LD SCORE REGRESSION, Medizin, Genome-wide association study, US CHILDREN, Genoma humà, Attention deficit disorder with hyperactivity in children, Medical and Health Sciences, Cohort Studies, 0302 clinical medicine, 2.1 Biological and endogenous factors, POLYGENIC RISK, Aetiology, Child, IDENTIFIES 11, SEXUAL-BEHAVIOR, Early Lifecourse & Genetic Epidemiology (EAGLE) Consortium, Pediatric, 0303 health sciences, education.field_of_study, Genome, Genetic Predisposition to Disease/genetics, 1184 Genetics, developmental biology, physiology, Brain, 3rd-DAS, Single Nucleotide, Biological Sciences, Polymorphism, Single Nucleotide/genetics, 3. Good health, Mental Health, Meta-analysis, Child, Preschool, Genetic Loci/genetics, Genome-Wide Association Study/methods, Trastorns per dèficit d'atenció amb hiperactivitat en els adults, Attention Deficit Disorder (ADD), Female, Attention Deficit Disorder with Hyperactivity/genetics, RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry, SDG 4 - Quality Education, Clinical psychology, Risk, Adolescent, DEFICIT HYPERACTIVITY DISORDER, Concordance, Population, PROVIDES INSIGHTS, QH426 Genetics, Biology, Quantitative trait locus, Brain/physiology, Polymorphism, Single Nucleotide, 23andMe Research Team, behavioral disciplines and activities, Gene Expression Regulation/genetics, Article, 150 000 MR Techniques in Brain Function, GENETIC ARCHITECTURE, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, Clinical Research, Behavioral and Social Science, mental disorders, medicine, Genetics, Attention deficit hyperactivity disorder, Humans, Genetic Predisposition to Disease, Polymorphism, education, Preschool, QH426, 030304 developmental biology, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], ASSOCIATION METAANALYSIS, Prevention, Human Genome, Case-control study, MAJOR DEPRESSION, medicine.disease, Attention Deficit Hyperactivity Disorder (ADHD), Genetic architecture, Brain Disorders, ADHD Working Group of the Psychiatric Genomics Consortium, Gene Expression Regulation, Attention Deficit Disorder with Hyperactivity, Genetic Loci, RC0321, Attention deficit disorder with hyperactivity in adults, 3111 Biomedicine, 030217 neurology & neurosurgery, Genome-Wide Association Study, Developmental Biology
Abstract

Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits. Postprint

Published
2019
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47. Improving genetic prediction by leveraging genetic correlations among human diseases and traits

Author

Maier, R. M., Zhu, Z., Lee, S. H., Trzaskowski, M., Ruderfer, D. M., Stahl, E. A., Ripke, S., Wray, N. R., Yang, J., Visscher, P. M., Robinson, M. R., Forstner, A. J., Mcquillin, A., Trubetskoy, V., Wang, W., Wang, Y., Coleman, J. R. I., Gaspar, H. A., Leeuw, C. A., Whitehead Pavlides, J. M., Olde Loohuis, L. M., Pers, T. H., Lee, P. H., Charney, A. W., Dobbyn, A. L., Huckins, L., Boocock, J., Giambartolomei, C., Roussos, P., Mullins, N., Awasthi, S., Agerbo, E., Als, T. D., Pedersen, C. B., Grove, J., Kupka, R., Regeer, E. J., Anjorin, A., Casas, M., Mahon, P. B., Allardyce, J., Escott-Price, V., Forty, L., Fraser, C., Kogevinas, M., Frank, J., Streit, F., Strohmaier, J., Treutlein, J., Witt, S. H., Kennedy, J. L., Strauss, J. S., Garnham, J., O Donovan, C., Slaney, C., Steinberg, S., Thorgeirsson, T. E., Hautzinger, M., Steffens, M., Perlis, R. H., Sánchez-Mora, C., Hipolito, M., Lawson, W. B., Nwulia, E. A., Levy, S. E., Foroud, T. M., Jamain, S., Young, A. H., Mckay, J. D., Albani, D., Zandi, P., Potash, J. B., Zhang, P., Raymond Depaulo, J., Bergen, S. E., Juréus, A., Karlsson, R., Kandaswamy, R., Mcguffin, P., Rivera, M., Lissowska, J., Cruceanu, C., Lucae, S., Cervantes, P., Budde, M., Gade, K., Heilbronner, U., Pedersen, M. G., Morris, D. W., Weickert, C. S., Weickert, T. W., Macintyre, D. J., Lawrence, J., Elvsåshagen, T., Smeland, O. B., Djurovic, S., Xi, S., Green, E. K., Czerski, P. M., Hauser, J., Xu, W., Vedder, H., Oruc, L., Spijker, A. T., Gordon, S. D., Medland, S. E., Curtis, D., Mühleisen, T. W., Badner, J. A., Scheftner, W. A., Sigurdsson, E., Schork, N. J., Schatzberg, A. F., Bækvad-Hansen, M., Bybjerg-Grauholm, J., Hansen, C. S., Knowles, J. A., Szelinger, S., Montgomery, G. W., Boks, M., Adolfsson, A. N., Hoffmann, P., Bauer, M., Pfennig, A., Leber, M., Kittel-Schneider, S., Reif, A., Del-Favero, J., Fischer, S. B., Herms, S., Reinbold, C. S., Degenhardt, F., Koller, A. C., Maaser, A., Ori, A. P. S., Dale, A. M., Fan, C. C., Greenwood, T. A., Nievergelt, C. M., Shehktman, T., Shilling, P. D., Byerley, W., Bunney, W., Alliey-Rodriguez, N., Clarke, T. K., Liu, C., Coryell, W., Akil, H., Burmeister, M., Flickinger, M., Li, J. Z., Mcinnis, M. G., Meng, F., Thompson, R. C., Watson, S. J., Zollner, S., Guan, W., Green, M. J., Craig, D., Sobell, J. L., Milani, L., Gordon-Smith, Katherine, Knott, Sarah, Perry, Amy, Parra, J. G., Mayoral, F., Rivas, F., Rice, J. P., Barchas, J. D., Børglum, A. D., Mortensen, P. B., Mors, O., Grigoroiu-Serbanescu, M., Bellivier, F., Etain, B., Leboyer, M., Ramos-Quiroga, J. A., Agartz, I., Amin, F., Azevedo, M. H., Bass, N., Black, D. W., Blackwood, D. H. R., Bruggeman, R., Buccola, N. G., Choudhury, K., Cloninger, C. R., Corvin, A., Craddock, N., Daly, M. J., Datta, S., Donohoe, G. J., Duan, J., Dudbridge, F., Fanous, A., Freedman, R., Freimer, N. B., Friedl, M., Gill, M., Gurling, H., Haan, L., Hamshere, M. L., Hartmann, A. M., Holmans, P. A., Kahn, R. S., Keller, M. C., Kenny, E., Kirov, G. K., Krabbendam, L., Krasucki, R., Lencz, T., Levinson, D. F., Lieberman, J. A., Lin, D. -Y, Linszen, D. H., Magnusson, P. K. E., Maier, W., Malhotra, A. K., Mattheisen, M., Mattingsdal, M., Mccarroll, S. A., Medeiros, H., Melle, I., Milanova, V., Myin-Germeys, I., Neale, B. M., Ophoff, R. A., Owen, M. J., Pimm, J., Purcell, S. M., Puri, V., Digby Quested, Rossin, L., Sanders, A. R., Shi, J., Sklar, P., St Clair, D., Stroup, T. S., Os, J., Wiersma, D., Zammit, S., Maier, Robert M, Zhu, Zhihong, Lee, Sang Hong, Trzaskowski, Maciej, Ruderfer, Douglas M, Stahl, Eli A, Ripke, Stephan, Wray, Naomi R, Yang, Jian, Visscher, Peter M, Robinson, Matthew R, Bipolar Disorder Working Grp Psy, Schizophrenia Working Grp Psychiat, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, APH - Mental Health, ANS - Complex Trait Genetics, Adult Psychiatry, and Psychiatry

Subjects
0301 basic medicine, Bipolar Disorder, Chemistry(all), Science, General Physics and Astronomy, Genomics, Genome-wide association study, Computational biology, Biology, Physics and Astronomy(all), Risk Assessment, Biochemistry, General Biochemistry, Genetics and Molecular Biology, Article, predictive medicine, quantitative trait, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Pleiotropy, Genetic Pleiotropy, Humans, Genetic Predisposition to Disease, lcsh:Science, Multidisciplinary, Models, Statistical, Bipolar Disorder/genetics, Genome-Wide Association Study, Schizophrenia/genetics, Biochemistry, Genetics and Molecular Biology(all), General Chemistry, Precision medicine, R1, Biobank, 3. Good health, genome wide association studies, 030104 developmental biology, Trait, Schizophrenia, statistical methods, lcsh:Q, Risk assessment, 030217 neurology & neurosurgery, Genetics and Molecular Biology(all)
Abstract

Genomic prediction has the potential to contribute to precision medicine. However, to date, the utility of such predictors is limited due to low accuracy for most traits. Here theory and simulation study are used to demonstrate that widespread pleiotropy among phenotypes can be utilised to improve genomic risk prediction. We show how a genetic predictor can be created as a weighted index that combines published genome-wide association study (GWAS) summary statistics across many different traits. We apply this framework to predict risk of schizophrenia and bipolar disorder in the Psychiatric Genomics consortium data, finding substantial heterogeneity in prediction accuracy increases across cohorts. For six additional phenotypes in the UK Biobank data, we find increases in prediction accuracy ranging from 0.7% for height to 47% for type 2 diabetes, when using a multi-trait predictor that combines published summary statistics from multiple traits, as compared to a predictor based only on one trait., Genetic prediction of complex traits so far has limited accuracy because of insufficient understanding of the genetic risk. Here, Maier et al. develop an improved method for trait prediction that makes use of genetic correlations between traits and apply it to summary statistics of psychiatric diseases.

Published
2018
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48. P.354 Elevated ceramide plasma level in major depression and bipolar disorder indicate an increased risk for metabolic dysregulation

Author

Brunkhorst-Kanaan, N., primary, Klatt-Schreiner, K., additional, Schröter, K., additional, Hackel, J., additional, Trautmann, S., additional, Hahnefeld, L., additional, Wicker, S., additional, Reif, A., additional, Thomas, D., additional, Geisslinger, G., additional, Kittel-Schneider, S., additional, and Tegeder, I., additional

Published
2019
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50. Cross-species models of attention-deficit/hyperactivity disorder and autism spectrum disorder: lessons from CNTNAP2, ADGRL3, and PARK2

Author

Vecchia, E. Dalla, Mortimer, N., Palladino, V.S., Kittel-Schneider, S., Lesch, K.P., Reif, A., Schenck, A., Norton, W.H., Vecchia, E. Dalla, Mortimer, N., Palladino, V.S., Kittel-Schneider, S., Lesch, K.P., Reif, A., Schenck, A., and Norton, W.H.

Abstract

Contains fulltext : 202781.pdf (Publisher’s version ) (Open Access), Animal and cellular models are essential tools for all areas of biological research including neuroscience. Model systems can also be used to investigate the pathophysiology of psychiatric disorders such as attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). In this review, we provide a summary of animal and cellular models for three genes linked to ADHD and ASD in human patients - CNTNAP2, ADGRL3, and PARK2. We also highlight the strengths and weaknesses of each model system. By bringing together behavioral and neurobiological data, we demonstrate how a cross-species approach can provide integrated insights into gene function and the pathogenesis of ADHD and ASD. The knowledge gained from transgenic models will be essential to discover and validate new treatment targets for these disorders.

Published
2019

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