103 results on '"Mentch F."'
Search Results
2. Targeted resequencing identifies defective variants of decoy receptor 3 in pediatric-onset inflammatory bowel disease
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Cardinale, C J, Wei, Z, Panossian, S, Wang, F, Kim, C E, Mentch, F D, Chiavacci, R M, Kachelries, K E, Pandey, R, Grant, S F A, Baldassano, R N, and Hakonarson, H
- Published
- 2013
- Full Text
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3. 366 Adverse reproductive outcomes among women with hidradenitis suppurativa
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Colvin, A., primary, Dabela, E., additional, Khan, A., additional, Hayes, M., additional, Connolly, J., additional, Mentch, F., additional, Almoguera, B., additional, Hakonarson, H., additional, Mukherjee, E., additional, Hripcsak, G., additional, Weng, C., additional, Kiryluk, K., additional, Wheless, L., additional, and Petukhova, L., additional
- Published
- 2021
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4. 570 A genome-wide association study in an African American cohort implicates IL-12A in acne
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Khan, A., primary, McGovern, J., additional, Yang, Z., additional, Wang, C., additional, Hughes, T., additional, Dabela, E., additional, Garzon, M.C., additional, Lauren, C.T., additional, Levin, L.E., additional, Dai, Z., additional, Hayes, M., additional, Connolly, J., additional, Mentch, F., additional, Almoguera, B., additional, Sleiman, P., additional, Hakonarson, H., additional, Denny, J., additional, Love, J.C., additional, Shalek, A.K., additional, Hripcsak, G., additional, Weng, C., additional, Ionita-Laza, I., additional, Kiryluk, K., additional, and Petukhova, L., additional
- Published
- 2021
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5. 328 Data driven approach identifies hidradenitis suppurativa subtypes in electronic health records
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Bell, A., primary, Babbush, K., additional, Khan, A., additional, Hayes, M., additional, Connolly, J., additional, Mentch, F., additional, Sleiman, P., additional, Hakonarson, H., additional, Mukherjee, E., additional, Hripcsak, G., additional, Kiryluk, K., additional, Weng, C., additional, Cohen, S., additional, Wheless, L., additional, and Petukhova, L., additional
- Published
- 2021
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6. 171 Hidradenitis suppurativa genome-wide association study
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Khan, A., primary, Lu, C.P., additional, Hayes, M., additional, Connolly, J., additional, Mentch, F., additional, Sleiman, P., additional, Hakonarson, H., additional, Mukherjee, E., additional, Weng, C., additional, Hripcsak, G., additional, Kiryluk, K., additional, Wheless, L., additional, and Petukhova, L., additional
- Published
- 2021
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7. Response to Li and Hopper.
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Thomas M., Sakoda L.C., Hoffmeister M., Rosenthal E.A., Lee J.K., van Duijnhoven F.J.B., Platz E.A., Wu A.H., Dampier C.H., de la Chapelle A., Wolk A., Joshi A.D., Burnett-Hartman A., Gsur A., Lindblom A., Castells A., Win A.K., Namjou B., Van Guelpen B., Tangen C.M., He Q., Li C.I., Schafmayer C., Joshu C.E., Ulrich C.M., Bishop D.T., Buchanan D.D., Schaid D., Drew D.A., Muller D.C., Duggan D., Crosslin D.R., Albanes D., Giovannucci E.L., Larson E., Qu F., Mentch F., Giles G.G., Hakonarson H., Hampel H., Stanaway I.B., Figueiredo J.C., Huyghe J.R., Minnier J., Chang-Claude J., Hampe J., Harley J.B., Visvanathan K., Curtis K.R., Offit K., Li L., Le Marchand L., Vodickova L., Gunter M.J., Jenkins M.A., Slattery M.L., Lemire M., Woods M.O., Song M., Murphy N., Lindor N.M., Dikilitas O., Pharoah P.D.P., Campbell P.T., Newcomb P.A., Milne R.L., MacInnis R.J., Castellvi-Bel S., Ogino S., Berndt S.I., Bezieau S., Thibodeau S.N., Gallinger S.J., Zaidi S.H., Harrison T.A., Keku T.O., Hudson T.J., Vymetalkova V., Moreno V., Martin V., Arndt V., Wei W.-Q., Chung W., Su Y.-R., Hayes R.B., White E., Vodicka P., Casey G., Gruber S.B., Schoen R.E., Chan A.T., Potter J.D., Brenner H., Jarvik G.P., Corley D.A., Peters U., Hsu L., Thomas M., Sakoda L.C., Hoffmeister M., Rosenthal E.A., Lee J.K., van Duijnhoven F.J.B., Platz E.A., Wu A.H., Dampier C.H., de la Chapelle A., Wolk A., Joshi A.D., Burnett-Hartman A., Gsur A., Lindblom A., Castells A., Win A.K., Namjou B., Van Guelpen B., Tangen C.M., He Q., Li C.I., Schafmayer C., Joshu C.E., Ulrich C.M., Bishop D.T., Buchanan D.D., Schaid D., Drew D.A., Muller D.C., Duggan D., Crosslin D.R., Albanes D., Giovannucci E.L., Larson E., Qu F., Mentch F., Giles G.G., Hakonarson H., Hampel H., Stanaway I.B., Figueiredo J.C., Huyghe J.R., Minnier J., Chang-Claude J., Hampe J., Harley J.B., Visvanathan K., Curtis K.R., Offit K., Li L., Le Marchand L., Vodickova L., Gunter M.J., Jenkins M.A., Slattery M.L., Lemire M., Woods M.O., Song M., Murphy N., Lindor N.M., Dikilitas O., Pharoah P.D.P., Campbell P.T., Newcomb P.A., Milne R.L., MacInnis R.J., Castellvi-Bel S., Ogino S., Berndt S.I., Bezieau S., Thibodeau S.N., Gallinger S.J., Zaidi S.H., Harrison T.A., Keku T.O., Hudson T.J., Vymetalkova V., Moreno V., Martin V., Arndt V., Wei W.-Q., Chung W., Su Y.-R., Hayes R.B., White E., Vodicka P., Casey G., Gruber S.B., Schoen R.E., Chan A.T., Potter J.D., Brenner H., Jarvik G.P., Corley D.A., Peters U., and Hsu L.
- Published
- 2021
8. Genome-wide Modeling of Polygenic Risk Score in Colorectal Cancer Risk.
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Huyghe J.R., Thomas M., Sakoda L.C., Hoffmeister M., Rosenthal E.A., Lee J.K., van Duijnhoven F.J.B., Platz E.A., Wu A.H., Dampier C.H., de la Chapelle A., Wolk A., Joshi A.D., Burnett-Hartman A., Gsur A., Lindblom A., Castells A., Win A.K., Namjou B., Van Guelpen B., Tangen C.M., He Q., Li C.I., Schafmayer C., Joshu C.E., Ulrich C.M., Bishop D.T., Buchanan D.D., Schaid D., Drew D.A., Muller D.C., Duggan D., Crosslin D.R., Albanes D., Giovannucci E.L., Larson E., Qu F., Mentch F., Giles G.G., Hakonarson H., Hampel H., Stanaway I.B., Figueiredo J.C., Minnier J., Chang-Claude J., Hampe J., Harley J.B., Visvanathan K., Curtis K.R., Offit K., Li L., Le Marchand L., Vodickova L., Gunter M.J., Jenkins M.A., Slattery M.L., Lemire M., Woods M.O., Song M., Murphy N., Lindor N.M., Dikilitas O., Pharoah P.D.P., Campbell P.T., Newcomb P.A., Milne R.L., MacInnis R.J., Castellvi-Bel S., Ogino S., Berndt S.I., Bezieau S., Thibodeau S.N., Gallinger S.J., Zaidi S.H., Harrison T.A., Keku T.O., Hudson T.J., Vymetalkova V., Moreno V., Martin V., Arndt V., Wei W.-Q., Chung W., Su Y.-R., Hayes R.B., White E., Vodicka P., Casey G., Gruber S.B., Schoen R.E., Chan A.T., Potter J.D., Brenner H., Jarvik G.P., Corley D.A., Peters U., Hsu L., Huyghe J.R., Thomas M., Sakoda L.C., Hoffmeister M., Rosenthal E.A., Lee J.K., van Duijnhoven F.J.B., Platz E.A., Wu A.H., Dampier C.H., de la Chapelle A., Wolk A., Joshi A.D., Burnett-Hartman A., Gsur A., Lindblom A., Castells A., Win A.K., Namjou B., Van Guelpen B., Tangen C.M., He Q., Li C.I., Schafmayer C., Joshu C.E., Ulrich C.M., Bishop D.T., Buchanan D.D., Schaid D., Drew D.A., Muller D.C., Duggan D., Crosslin D.R., Albanes D., Giovannucci E.L., Larson E., Qu F., Mentch F., Giles G.G., Hakonarson H., Hampel H., Stanaway I.B., Figueiredo J.C., Minnier J., Chang-Claude J., Hampe J., Harley J.B., Visvanathan K., Curtis K.R., Offit K., Li L., Le Marchand L., Vodickova L., Gunter M.J., Jenkins M.A., Slattery M.L., Lemire M., Woods M.O., Song M., Murphy N., Lindor N.M., Dikilitas O., Pharoah P.D.P., Campbell P.T., Newcomb P.A., Milne R.L., MacInnis R.J., Castellvi-Bel S., Ogino S., Berndt S.I., Bezieau S., Thibodeau S.N., Gallinger S.J., Zaidi S.H., Harrison T.A., Keku T.O., Hudson T.J., Vymetalkova V., Moreno V., Martin V., Arndt V., Wei W.-Q., Chung W., Su Y.-R., Hayes R.B., White E., Vodicka P., Casey G., Gruber S.B., Schoen R.E., Chan A.T., Potter J.D., Brenner H., Jarvik G.P., Corley D.A., Peters U., and Hsu L.
- Abstract
Accurate colorectal cancer (CRC) risk prediction models are critical for identifying individuals at low and high risk of developing CRC, as they can then be offered targeted screening and interventions to address their risks of developing disease (if they are in a high-risk group) and avoid unnecessary screening and interventions (if they are in a low-risk group). As it is likely that thousands of genetic variants contribute to CRC risk, it is clinically important to investigate whether these genetic variants can be used jointly for CRC risk prediction. In this paper, we derived and compared different approaches to generating predictive polygenic risk scores (PRS) from genome-wide association studies (GWASs) including 55,105 CRC-affected case subjects and 65,079 control subjects of European ancestry. We built the PRS in three ways, using (1) 140 previously identified and validated CRC loci; (2) SNP selection based on linkage disequilibrium (LD) clumping followed by machine-learning approaches; and (3) LDpred, a Bayesian approach for genome-wide risk prediction. We tested the PRS in an independent cohort of 101,987 individuals with 1,699 CRC-affected case subjects. The discriminatory accuracy, calculated by the age- and sex-adjusted area under the receiver operating characteristics curve (AUC), was highest for the LDpred-derived PRS (AUC = 0.654) including nearly 1.2 M genetic variants (the proportion of causal genetic variants for CRC assumed to be 0.003), whereas the PRS of the 140 known variants identified from GWASs had the lowest AUC (AUC = 0.629). Based on the LDpred-derived PRS, we are able to identify 30% of individuals without a family history as having risk for CRC similar to those with a family history of CRC, whereas the PRS based on known GWAS variants identified only top 10% as having a similar relative risk. About 90% of these individuals have no family history and would have been considered average risk under current screening guidelines, but might be
- Published
- 2020
9. 265 Genome-wide association study of hidradenitis suppurativa in a multi-ethnic cohort
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Khan, A., primary, Hayes, M., additional, Connolly, J., additional, Mentch, F., additional, Sleiman, P., additional, Hakonarson, H., additional, Wang, C., additional, Hripcsak, G., additional, Kiryluk, K., additional, and Petukhova, L., additional
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- 2020
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10. Genetic association of primary non-response to Anti-TNFα therapy in patients with Inflammatory Bowel Disease
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De, T., primary, Zhang, H., additional, Alarcon, C., additional, Lec, B., additional, Avitia, J., additional, Smithberger, E., additional, Chen, Chuyu, additional, Horvath, M., additional, Kwan, S., additional, Young, M., additional, Adhikari, S., additional, Kwon, J. H., additional, Pacheco, J., additional, Jarvik, G.P., additional, Wei, W., additional, Mentch, F., additional, Hakonarson, H., additional, Sleiman, P., additional, Gordon, A.S., additional, Harley, J., additional, Linneman, J. G., additional, Hebbring, S., additional, Parisiadou, L., additional, and Perera, M. A., additional
- Published
- 2020
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11. Genome-Wide Association Study Detects Common SNP Among Pediatric Patients with Obstructive Sleep Apnea
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Quinlan, C., primary, Chang, X., additional, Mentch, F., additional, and Hakonarson, H., additional
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- 2020
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12. 001 Genome-wide association study of acne inversa in a multi-ethnic cohort
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Khan, A., primary, Hayes, M.G., additional, Connolly, J., additional, Mentch, F., additional, Sleiman, P., additional, Hakonarson, H., additional, Denny, J., additional, Hripcsak, G.M., additional, Weng, C., additional, Kiryluk, K., additional, and Petukhova, L., additional
- Published
- 2019
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13. 854 GWAS of acne vulgaris among African Americans
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Khan, A., primary, Hayes, M., additional, Connolly, J., additional, Mentch, F., additional, Almoguera, B., additional, Hakonarson, H., additional, Denny, J., additional, Wang, C., additional, Hripcsak, G., additional, Kiryluk, K., additional, and Petukhova, L., additional
- Published
- 2019
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14. A novel common variant in DCST2 is associated with length in early life and height in adulthood
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van der Valk, R., Kreiner-Møller, E., Kooijman, M., Guxens, M., Stergiakouli, E., Sääf, A., Bradfield, J., Geller, F., Hayes, M., Cousminer, D., Körner, A., Thiering, E., Curtin, J., Myhre, R., Huikari, V., Joro, R., Kerkhof, M., Warrington, N., Pitkänen, N., Ntalla, I., Horikoshi, M., Veijola, R., Freathy, R., Teo, Y., Barton, S., Evans, D., Kemp, J., St Pourcain, B., Ring, S., Davey Smith, G., Bergström, A., Kull, I., Hakonarson, H., Mentch, F., Bisgaard, H., Chawes, B., Stokholm, J., Waage, J., Eriksen, P., Sevelsted, A., Melbye, M., van Duijn, C., Medina-Gomez, C., Hofman, A., de Jongste, J., Taal, H., Uitterlinden, A., Armstrong, L., Eriksson, J., Palotie, A., Bustamante, M., Estivill, X., Gonzalez, J., Llop, S., Kiess, W., Mahajan, A., Flexeder, C., Tiesler, C., Murray, C., Simpson, A., Magnus, P., Sengpiel, V., Hartikainen, A., Keinanen-Kiukaanniemi, S., Lewin, A., Da Silva Couto Alves, A., Blakemore, A., Buxton, J., Kaakinen, M., Rodriguez, A., Sebert, S., Vaarasmaki, M., Lakka, T., Lindi, V., Gehring, U., Postma, D., Ang, W., Newnham, J., Lyytikäinen, L., Pahkala, K., Raitakari, O., Panoutsopoulou, K., Zeggini, E., Boomsma, D., Groen-Blokhuis, M., Ilonen, J., Franke, L., Hirschhorn, J., Pers, T., Liang, L., Huang, J., Hocher, B., Knip, M., Saw, S., Holloway, J., Melén, E., Grant, S., Feenstra, B., Lowe, W., Widén, E., Sergeyev, E., Grallert, H., Custovic, A., Jacobsson, B., Jarvelin, M., Atalay, M., Koppelman, G., Pennell, C., Niinikoski, H., Dedoussis, G., Mccarthy, M., Frayling, T., Sunyer, J., Timpson, N., Rivadeneira, F., Bønnelykke, K., Jaddoe, V., and Early Growth Genetics (EGG) Consortium
- Abstract
Common genetic variants have been identified for adult height, but not much is known about the genetics of skeletal growth in early life. To identify common genetic variants that influence fetal skeletal growth, we meta-analyzed 22 genome-wide association studies (Stage 1; N = 28 459). We identified seven independent top single nucleotide polymorphisms (SNPs) (P < 1 × 10(-6)) for birth length, of which three were novel and four were in or near loci known to be associated with adult height (LCORL, PTCH1, GPR126 and HMGA2). The three novel SNPs were followed-up in nine replication studies (Stage 2; N = 11 995), with rs905938 in DC-STAMP domain containing 2 (DCST2) genome-wide significantly associated with birth length in a joint analysis (Stages 1 + 2; β = 0.046, SE = 0.008, P = 2.46 × 10(-8), explained variance = 0.05%). Rs905938 was also associated with infant length (N = 28 228; P = 5.54 × 10(-4)) and adult height (N = 127 513; P = 1.45 × 10(-5)). DCST2 is a DC-STAMP-like protein family member and DC-STAMP is an osteoclast cell-fusion regulator. Polygenic scores based on 180 SNPs previously associated with human adult stature explained 0.13% of variance in birth length. The same SNPs explained 2.95% of the variance of infant length. Of the 180 known adult height loci, 11 were genome-wide significantly associated with infant length (SF3B4, LCORL, SPAG17, C6orf173, PTCH1, GDF5, ZNFX1, HHIP, ACAN, HLA locus and HMGA2). This study highlights that common variation in DCST2 influences variation in early growth and adult height.
- Published
- 2015
15. Variants in CXCR4 associate with juvenile idiopathic arthritis susceptibility
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Finkel, TH, Li, J, Wei, Z, Wang, W, Zhang, H, Behrens, EM, Reuschel, EL, Limou, S, Wise, C, Punaro, M, Becker, ML, Munro, JE, Flato, B, Forre, O, Thompson, SD, Langefeld, CD, Glass, DN, Glessner, JT, Kim, CE, Frackelton, E, Shivers, DK, Thomas, KA, Chiavacci, RM, Hou, C, Xu, K, Snyder, J, Qiu, H, Mentch, F, Wang, K, Winkler, CA, Lie, BA, Ellis, JA, Hakonarson, H, Finkel, TH, Li, J, Wei, Z, Wang, W, Zhang, H, Behrens, EM, Reuschel, EL, Limou, S, Wise, C, Punaro, M, Becker, ML, Munro, JE, Flato, B, Forre, O, Thompson, SD, Langefeld, CD, Glass, DN, Glessner, JT, Kim, CE, Frackelton, E, Shivers, DK, Thomas, KA, Chiavacci, RM, Hou, C, Xu, K, Snyder, J, Qiu, H, Mentch, F, Wang, K, Winkler, CA, Lie, BA, Ellis, JA, and Hakonarson, H
- Abstract
BACKGROUND: Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease among children, the etiology of which involves a strong genetic component, but much of the underlying genetic determinants still remain unknown. Our aim was to identify novel genetic variants that predispose to JIA. METHODS: We performed a genome-wide association study (GWAS) and replication in a total of 1166 JIA cases and 9500 unrelated controls of European ancestry. Correlation of SNP genotype and gene expression was investigated. Then we conducted targeted resequencing of a candidate locus, among a subset of 480 cases and 480 controls. SUM test was performed to evaluate the association of the identified rare functional variants. RESULTS: The CXCR4 locus on 2q22.1 was found to be significantly associated with JIA, peaking at SNP rs953387. However, this result is subjected to subpopulation stratification within the subjects of European ancestry. After adjusting for principal components, nominal significant association remained (p < 10(-4)). Because of its interesting known function in immune regulation, we carried out further analyses to assess its relationship with JIA. Expression of CXCR4 was correlated with CXCR4 rs953387 genotypes in lymphoblastoid cell lines (p = 0.014) and T-cells (p = 0.0054). In addition, rare non-synonymous and stop-gain sequence variants in CXCR4, putatively damaging for CXCR4 function, were significantly enriched in JIA cases (p = 0.015). CONCLUSION: Our results suggest the association of CXCR4 variants with JIA, implicating that this gene may be involved in the pathogenesis of autoimmune disease. However, because this locus is subjected to population stratification within the subjects of European ancestry, additional replication is still necessary for this locus to be considered a true risk locus for JIA. This cell-surface chemokine receptor has already been targeted in other diseases and may serve as a tractable therapeutic target for a specif
- Published
- 2016
16. The impact of the metabotropic glutamate receptor and other gene family interaction networks on autism
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Hadley, D., Wu, Z.L., Kao, C., Kini, A., Mohamed-Hadley, A., Thomas, K., Vazquez, L., Qiu, H., Mentch, F., Pellegrino, R., Kim, C., Connolly, J., Glessner, J., Hakonarson, H., Pinto, D., Merikangas, A., Klei, L., Vorstman, J.A., Thompson, A., Regan, R., Pagnamenta, A.T., Oliveira, B., Magalhaes, T.R., Gilbert, J., Duketis, E., De Jonge, M.V., Cuccaro, M., Correia, C.T., Conroy, J., Conceição, I.C., Chiocchetti, A.G., Casey, J.P., Bolshakova, N., Bacchelli, E., Anney, R., Zwaigenbaum, L., Wittemeyer, K., Wallace, S., Engeland, Hv, Soorya, L., Rogé, B., Roberts, W., Poustka, F., Mouga, S., Minshew, N., McGrew, S.G., Lord, C., Leboyer, M., Le Couteur, A.S., Kolevzon, A., Jacob, S., Guter, S., Green, J., Green, A., Gillberg, C., Fernandez, B.A., Duque, F., Delorme, R., Dawson, G., Café, C., Brennan, S., Bourgeron, T., Bolton, P.F., Bölte, S., Bernier, R., Baird, G., Bailey, A.J., Anagnostou, E., Almeida, J., Wijsman, E.M., Vieland, V.J., Vicente, A.M., Schellenberg, G.D., Pericak-Vance, M., Paterson, A.D., Parr, J.R., Oliveira, G., Correia, C., Nurnberger, J.I., Monaco, A.P., Maestrini, E., Klauck, S.M., Haines, J.L., Geschwind, D.H., Freitag, C.M., Folstein, S.E., Ennis, S., Coon, H., Battaglia, A., Szatmari, P., Sutcliffe, J.S., Hallmayer, J., Gill, M., Cook, E.H., Buxbaum, J.D., Devlin, B., Gallagher, L., Betancur, C., and Scherer, S.W.
- Subjects
Autism ,Perturbações do Desenvolvimento Infantil e Saúde Mental - Abstract
Although multiple reports show that defective genetic networks underlie the aetiology of autism, few have translated into pharmacotherapeutic opportunities. Since drugs compete with endogenous small molecules for protein binding, many successful drugs target large gene families with multiple drug binding sites. Here we search for defective gene family interaction networks (GFINs) in 6,742 patients with the ASDs relative to 12,544 neurologically normal controls, to find potentially druggable genetic targets. We find significant enrichment of structural defects (P≤2.40E-09, 1.8-fold enrichment) in the metabotropic glutamate receptor (GRM) GFIN, previously observed to impact attention deficit hyperactivity disorder (ADHD) and schizophrenia. Also, the MXD-MYC-MAX network of genes, previously implicated in cancer, is significantly enriched (P≤3.83E-23, 2.5-fold enrichment), as is the calmodulin 1 (CALM1) gene interaction network (P≤4.16E-04, 14.4-fold enrichment), which regulates voltage-independent calcium-activated action potentials at the neuronal synapse. We find that multiple defective gene family interactions underlie autism, presenting new translational opportunities to explore for therapeutic interventions.
- Published
- 2014
17. Meta-analysis of genome-wide association studies identifies three new risk loci for atopic dermatitis
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Paternoster, L, Standl, M, Chen, CM, Ramasamy, A, Bønnelykke, K, Duijts, L, Ferreira, MA, Alves, AC, Thyssen, JP, Albrecht, E, Baurecht, H, Feenstra, B, Sleiman, PM, Hysi, P, Warrington, NM, Curjuric, I, Myhre, R, Curtin, JA, Groen-Blokhuis, MM, Kerkhof, M, Sääf, A, Franke, A, Ellinghaus, D, Fölster-Holst, R, Dermitzakis, E, Montgomery, SB, Prokisch, H, Heim, K, Hartikainen, AL, Pouta, A, Pekkanen, J, Blakemore, AI, Buxton, JL, Kaakinen, M, Duffy, DL, Madden, PA, Heath, AC, Montgomery, GW, Thompson, PJ, Matheson, MC, Le Souëf, P, Australian Asthma Genetics Consortium (AAGC), St Pourcain, B, Smith, GD, Henderson, J, Kemp, JP, Timpson, NJ, Deloukas, P, Ring, SM, Wichmann, HE, Müller-Nurasyid, M, Novak, N, Klopp, N, Rodríguez, E, McArdle, W, Linneberg, A, Menné, T, Nohr, EA, Hofman, A, Uitterlinden, AG, van Duijn, CM, Rivadeneira, F, de Jongste, JC, van der Valk, RJ, Wjst, M, Jogi, R, Geller, F, Boyd, HA, Murray, JC, Kim, C, Mentch, F, March, M, Mangino, M, Spector, TD, Bataille, V, Pennell, CE, Holt, PG, Sly, P, Tiesler, CM, Thiering, E, Illig, T, Imboden, M, Nystad, W, Simpson, A, Hottenga, JJ, Postma, D, Koppelman, GH, Smit, HA, Söderhäll, C, Chawes, B, Kreiner-Møller, E, Bisgaard, H, Melén, E, Boomsma, DI, Custovic, A, Jacobsson, B, Probst-Hensch, NM, Palmer, LJ, Glass, D, Hakonarson, H, Melbye, M, Jarvis, DL, Jaddoe, VW, Gieger, C, Genetics of Overweight Young Adults (GOYA) Consortium, Strachan, DP, Martin, NG, Jarvelin, MR, Heinrich, J, Evans, DM, Weidinger, S, and EArly Genetics & Lifecourse Epidemiology (EAGLE) Consortium
- Abstract
Atopic dermatitis (AD) is a commonly occurring chronic skin disease with high heritability. Apart from filaggrin (FLG), the genes influencing atopic dermatitis are largely unknown. We conducted a genome-wide association meta-analysis of 5,606 affected individuals and 20,565 controls from 16 population-based cohorts and then examined the ten most strongly associated new susceptibility loci in an additional 5,419 affected individuals and 19,833 controls from 14 studies. Three SNPs reached genome-wide significance in the discovery and replication cohorts combined, including rs479844 upstream of OVOL1 (odds ratio (OR) = 0.88, P = 1.1 × 10−13) and rs2164983 near ACTL9 (OR = 1.16, P = 7.1 × 10−9), both of which are near genes that have been implicated in epidermal proliferation and differentiation, as well as rs2897442 in KIF3A within the cytokine cluster at 5q31.1 (OR = 1.11, P = 3.8 × 10−8). We also replicated association with the FLG locus and with two recently identified association signals at 11q13.5 (rs7927894; P = 0.008) and 20q13.33 (rs6010620; P = 0.002). Our results underline the importance of both epidermal barrier function and immune dysregulation in atopic dermatitis pathogenesis.
- Published
- 2012
18. Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder.
- Author
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Elia, J., Glessner, J.T., Wang, K., Takahashi, N., Shtir, C.J., Hadley, D., Sleiman, P.M., Zhang, H., Kim, C.E., Robison, R., Lyon, G.J., Flory, J.H., Bradfield, J.P., Imielinski, M., Hou, C., Frackelton, E.C., Chiavacci, R.M., Sakurai, T., Rabin, C., Middleton, F.A., Thomas, K.A., Garris, M., Mentch, F., Freitag, C.M., Steinhausen, H.C., Todorov, A.A., Reif, A., Rothenberger, A., Franke, B., Mick, E.O., Roeyers, H., Buitelaar, J.K., Lesch, K.P., Banaschewski, T., Ebstein, R.P., Mulas, F., Oades, R.D., Sergeant, J.A., Sonuga-Barke, E.J.S., Renner, T.J., Romanos, M., Romanos, J., Warnke, A., Walitza, S., Meyer, J., Palmason, H., Seitz, C., Loo, S.K., Smalley, S.L., Biederman, J., Kent, L., Asherson, P., Anney, R.J., Gaynor, J.W., Shaw, P., Devoto, M., White, P.S., Grant, S.F., Buxbaum, J.D., Rapoport, J.L., Williams, N.M., Nelson, S.F., Faraone, S.V., Hakonarson, H., Elia, J., Glessner, J.T., Wang, K., Takahashi, N., Shtir, C.J., Hadley, D., Sleiman, P.M., Zhang, H., Kim, C.E., Robison, R., Lyon, G.J., Flory, J.H., Bradfield, J.P., Imielinski, M., Hou, C., Frackelton, E.C., Chiavacci, R.M., Sakurai, T., Rabin, C., Middleton, F.A., Thomas, K.A., Garris, M., Mentch, F., Freitag, C.M., Steinhausen, H.C., Todorov, A.A., Reif, A., Rothenberger, A., Franke, B., Mick, E.O., Roeyers, H., Buitelaar, J.K., Lesch, K.P., Banaschewski, T., Ebstein, R.P., Mulas, F., Oades, R.D., Sergeant, J.A., Sonuga-Barke, E.J.S., Renner, T.J., Romanos, M., Romanos, J., Warnke, A., Walitza, S., Meyer, J., Palmason, H., Seitz, C., Loo, S.K., Smalley, S.L., Biederman, J., Kent, L., Asherson, P., Anney, R.J., Gaynor, J.W., Shaw, P., Devoto, M., White, P.S., Grant, S.F., Buxbaum, J.D., Rapoport, J.L., Williams, N.M., Nelson, S.F., Faraone, S.V., and Hakonarson, H.
- Abstract
Item does not contain fulltext, Attention deficit hyperactivity disorder (ADHD) is a common, heritable neuropsychiatric disorder of unknown etiology. We performed a whole-genome copy number variation (CNV) study on 1,013 cases with ADHD and 4,105 healthy children of European ancestry using 550,000 SNPs. We evaluated statistically significant findings in multiple independent cohorts, with a total of 2,493 cases with ADHD and 9,222 controls of European ancestry, using matched platforms. CNVs affecting metabotropic glutamate receptor genes were enriched across all cohorts (P = 2.1 x 10(-9)). We saw GRM5 (encoding glutamate receptor, metabotropic 5) deletions in ten cases and one control (P = 1.36 x 10(-6)). We saw GRM7 deletions in six cases, and we saw GRM8 deletions in eight cases and no controls. GRM1 was duplicated in eight cases. We experimentally validated the observed variants using quantitative RT-PCR. A gene network analysis showed that genes interacting with the genes in the GRM family are enriched for CNVs in approximately 10% of the cases (P = 4.38 x 10(-10)) after correction for occurrence in the controls. We identified rare recurrent CNVs affecting glutamatergic neurotransmission genes that were overrepresented in multiple ADHD cohorts.
- Published
- 2011
19. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis
- Author
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Sawcer, S., Hellenthal, G., Pirinen, M., Spencer, C.C.A., Patsopoulos, N.A., Moutsianas, L., Dilthey, A., Su, Z., Freeman, C., Hunt, S.E., Edkins, S., Gray, E., Booth, D.R., Potter, S.C., Goris, A., Band, G., Bang Oturai, A., Strange, A., Saarela, J., Bellenguez, C., Fontaine, B., Gillman, M., Hemmer, B., Gwilliam, R., Zipp, F., Jayakumar, A., Martin, R., Leslie, S., Hawkins, S., Giannoulatou, E., D’alfonso, S., Blackburn, H., Martinelli Boneschi, F., Liddle, J., Harbo, H.F., Perez, M.L., Spurkland, A., Waller, M.J., Mycko, M.P., Ricketts, M., Comabella, M., Hammond, N., Kockum, I., McCann, O.T., Ban, M., Whittaker, P., Kemppinen, A., Weston, P., Hawkins, C., Widaa, S., Zajicek, J., Dronov, S., Robertson, N., Bumpstead, S.J., Barcellos, L.F., Ravindrarajah, R., Abraham, R., Alfredsson, L., Ardlie, K., Aubin, C., Baker, A., Baker, K., Baranzini, S.E., Bergamaschi, L., Bergamaschi, R., Bernstein, A., Berthele, A., Boggild, M., Bradfield, J.P., Brassat, D., Broadley, S.A., Buck, D., Butzkueven, H., Capra, R., Carroll, W.M., Cavalla, P., Celius, E.G., Cepok, S., Chiavacci, R., Clerget-Darpoux, F., Clysters, K., Comi, G., Cossburn, M., Cournu-Rebeix, I., Cox, M.B., Cozen, W., Cree, B.A.C., Cross, A.H., Cusi, D., Daly, M.J., Davis, E., de Bakker, P.I.W., Debouverie, M., D’hooghe, M.B., Dixon, K., Dobosi, R., Dubois, B., Ellinghaus, D., Elovaara, I., Esposito, F., Fontenille, C., Foote, S., Franke, A., Galimberti, D., Ghezzi, A., Glessner, J., Gomez, R., Gout, O., Graham, C., Grant, S.F.A., Rosa Guerini, F., Hakonarson, H., Hall, P., Hamsten, A., Hartung, H-P, Heard, R.N., Heath, S., Hobart, J., Hoshi, M., Infante-Duarte, C., Ingram, G., Ingram, W., Islam, T., Jagodic, M., Kabesch, M., Kermode, A.G., Kilpatrick, T.J., Kim, C., Klopp, N., Koivisto, K., Larsson, M., Lathrop, M., Lechner-Scott, J.S., Leone, M.A., Leppä, V., Liljedahl, U., Lima Bomfim, I., Lincoln, R.R., Link, J., Liu, J., Lorentzen, Å.R., Lupoli, S., Macciardi, F., Mack, T., Marriott, M., Martinelli, V., Mason, D., McCauley, J.L., Mentch, F., Mero, I-L, Mihalova, T., Montalban, X., Mottershead, J., Myhr, K-M, Naldi, P., Ollier, W., Page, A., Palotie, A., Pelletier, J., Piccio, L., Pickersgill, T., Piehl, F., Pobywajlo, S., Quach, H.L., Ramsay, P.P., Reunanen, M., Reynolds, R., Rioux, J.D., Rodegher, M., Roesner, S., Rubio, J.P., Rückert, I-M, Salvetti, M., Salvi, E., Santaniello, A., Schaefer, C.A., Schreiber, S., Schulze, C., Scott, R.J., Sellebjerg, F., Selmaj, K.W., Sexton, D., Shen, L., Simms-Acuna, B., Skidmore, S., Sleiman, P.M.A., Smestad, C., Sørensen, P.S., Søndergaard, H.B., Stankovich, J., Strange, R.C., Sulonen, A-M, Sundqvist, E., Syvänen, A-C, Taddeo, F., Taylor, B., Blackwell, J.M., Tienari, P., Bramon, E., Tourbah, A., Brown, M.A., Tronczynska, E., Casas, J.P., Tubridy, N., Corvin, A., Vickery, J., Jankowski, J., Villoslada, P., Markus, H.S., Wang, K., Mathew, C.G., Wason, J., Palmer, C.N.A., Wichmann, H-E, Plomin, R., Willoughby, E., Rautanen, A., Winkelmann, J., Wittig, M., Trembath, R.C., Yaouanq, J., Viswanathan, A.C., Zhang, H., Wood, N.W., Zuvich, R., Deloukas, P., Langford, C., Duncanson, A., Oksenberg, J.R., Pericak-Vance, M.A., Haines, J.L., Olsson, T., Hillert, J., Ivinson, A.J., De Jager, P.L., Peltonen, L., Stewart, G.J., Hafler, D.A., Hauser, S.L., McVean, G., Donnelly, P., Compston, A., Sawcer, S., Hellenthal, G., Pirinen, M., Spencer, C.C.A., Patsopoulos, N.A., Moutsianas, L., Dilthey, A., Su, Z., Freeman, C., Hunt, S.E., Edkins, S., Gray, E., Booth, D.R., Potter, S.C., Goris, A., Band, G., Bang Oturai, A., Strange, A., Saarela, J., Bellenguez, C., Fontaine, B., Gillman, M., Hemmer, B., Gwilliam, R., Zipp, F., Jayakumar, A., Martin, R., Leslie, S., Hawkins, S., Giannoulatou, E., D’alfonso, S., Blackburn, H., Martinelli Boneschi, F., Liddle, J., Harbo, H.F., Perez, M.L., Spurkland, A., Waller, M.J., Mycko, M.P., Ricketts, M., Comabella, M., Hammond, N., Kockum, I., McCann, O.T., Ban, M., Whittaker, P., Kemppinen, A., Weston, P., Hawkins, C., Widaa, S., Zajicek, J., Dronov, S., Robertson, N., Bumpstead, S.J., Barcellos, L.F., Ravindrarajah, R., Abraham, R., Alfredsson, L., Ardlie, K., Aubin, C., Baker, A., Baker, K., Baranzini, S.E., Bergamaschi, L., Bergamaschi, R., Bernstein, A., Berthele, A., Boggild, M., Bradfield, J.P., Brassat, D., Broadley, S.A., Buck, D., Butzkueven, H., Capra, R., Carroll, W.M., Cavalla, P., Celius, E.G., Cepok, S., Chiavacci, R., Clerget-Darpoux, F., Clysters, K., Comi, G., Cossburn, M., Cournu-Rebeix, I., Cox, M.B., Cozen, W., Cree, B.A.C., Cross, A.H., Cusi, D., Daly, M.J., Davis, E., de Bakker, P.I.W., Debouverie, M., D’hooghe, M.B., Dixon, K., Dobosi, R., Dubois, B., Ellinghaus, D., Elovaara, I., Esposito, F., Fontenille, C., Foote, S., Franke, A., Galimberti, D., Ghezzi, A., Glessner, J., Gomez, R., Gout, O., Graham, C., Grant, S.F.A., Rosa Guerini, F., Hakonarson, H., Hall, P., Hamsten, A., Hartung, H-P, Heard, R.N., Heath, S., Hobart, J., Hoshi, M., Infante-Duarte, C., Ingram, G., Ingram, W., Islam, T., Jagodic, M., Kabesch, M., Kermode, A.G., Kilpatrick, T.J., Kim, C., Klopp, N., Koivisto, K., Larsson, M., Lathrop, M., Lechner-Scott, J.S., Leone, M.A., Leppä, V., Liljedahl, U., Lima Bomfim, I., Lincoln, R.R., Link, J., Liu, J., Lorentzen, Å.R., Lupoli, S., Macciardi, F., Mack, T., Marriott, M., Martinelli, V., Mason, D., McCauley, J.L., Mentch, F., Mero, I-L, Mihalova, T., Montalban, X., Mottershead, J., Myhr, K-M, Naldi, P., Ollier, W., Page, A., Palotie, A., Pelletier, J., Piccio, L., Pickersgill, T., Piehl, F., Pobywajlo, S., Quach, H.L., Ramsay, P.P., Reunanen, M., Reynolds, R., Rioux, J.D., Rodegher, M., Roesner, S., Rubio, J.P., Rückert, I-M, Salvetti, M., Salvi, E., Santaniello, A., Schaefer, C.A., Schreiber, S., Schulze, C., Scott, R.J., Sellebjerg, F., Selmaj, K.W., Sexton, D., Shen, L., Simms-Acuna, B., Skidmore, S., Sleiman, P.M.A., Smestad, C., Sørensen, P.S., Søndergaard, H.B., Stankovich, J., Strange, R.C., Sulonen, A-M, Sundqvist, E., Syvänen, A-C, Taddeo, F., Taylor, B., Blackwell, J.M., Tienari, P., Bramon, E., Tourbah, A., Brown, M.A., Tronczynska, E., Casas, J.P., Tubridy, N., Corvin, A., Vickery, J., Jankowski, J., Villoslada, P., Markus, H.S., Wang, K., Mathew, C.G., Wason, J., Palmer, C.N.A., Wichmann, H-E, Plomin, R., Willoughby, E., Rautanen, A., Winkelmann, J., Wittig, M., Trembath, R.C., Yaouanq, J., Viswanathan, A.C., Zhang, H., Wood, N.W., Zuvich, R., Deloukas, P., Langford, C., Duncanson, A., Oksenberg, J.R., Pericak-Vance, M.A., Haines, J.L., Olsson, T., Hillert, J., Ivinson, A.J., De Jager, P.L., Peltonen, L., Stewart, G.J., Hafler, D.A., Hauser, S.L., McVean, G., Donnelly, P., and Compston, A.
- Abstract
Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability1. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals2, 3, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk4. Modestly powered genome-wide association studies (GWAS)5, 6, 7, 8, 9, 10 have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility11. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
- Published
- 2011
20. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis
- Author
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Sawcer, S, Hellenthal, G, Pirinen, M, Spencer, CCA, Patsopoulos, NA, Moutsianas, L, Dilthey, A, Su, Z, Freeman, C, Hunt, SE, Edkins, S, Gray, E, Booth, DR, Potter, SC, Goris, A, Band, G, Oturai, AB, Strange, A, Saarela, J, Bellenguez, C, Fontaine, B, Gillman, M, Hemmer, B, Gwilliam, R, Zipp, F, Jayakumar, A, Martin, R, Leslie, S, Hawkins, S, Giannoulatou, E, D'alfonso, S, Blackburn, H, Boneschi, FM, Liddle, J, Harbo, HF, Perez, ML, Spurkland, A, Waller, MJ, Mycko, MP, Ricketts, M, Comabella, M, Hammond, N, Kockum, I, McCann, OT, Ban, M, Whittaker, P, Kemppinen, A, Weston, P, Hawkins, C, Widaa, S, Zajicek, J, Dronov, S, Robertson, N, Bumpstead, SJ, Barcellos, LF, Ravindrarajah, R, Abraham, R, Alfredsson, L, Ardlie, K, Aubin, C, Baker, A, Baker, K, Baranzini, SE, Bergamaschi, L, Bergamaschi, R, Bernstein, A, Berthele, A, Boggild, M, Bradfield, JP, Brassat, D, Broadley, SA, Buck, D, Butzkueven, H, Capra, R, Carroll, WM, Cavalla, P, Celius, EG, Cepok, S, Chiavacci, R, Clerget-Darpoux, F, Clysters, K, Comi, G, Cossburn, M, Cournu-Rebeix, I, Cox, MB, Cozen, W, Cree, BAC, Cross, AH, Cusi, D, Daly, MJ, Davis, E, de Bakker, PIW, Debouverie, M, D'hooghe, MB, Dixon, K, Dobosi, R, Dubois, B, Ellinghaus, D, Elovaara, I, Esposito, F, Fontenille, C, Foote, S, Franke, A, Galimberti, D, Ghezzi, A, Glessner, J, Gomez, R, Gout, O, Graham, C, Grant, SFA, Guerini, FR, Hakonarson, H, Hall, P, Hamsten, A, Hartung, H-P, Heard, RN, Heath, S, Hobart, J, Hoshi, M, Infante-Duarte, C, Ingram, G, Ingram, W, Islam, T, Jagodic, M, Kabesch, M, Kermode, AG, Kilpatrick, TJ, Kim, C, Klopp, N, Koivisto, K, Larsson, M, Lathrop, M, Lechner-Scott, JS, Leone, MA, Leppa, V, Liljedahl, U, Bomfim, IL, Lincoln, RR, Link, J, Liu, J, Lorentzen, AR, Lupoli, S, Macciardi, F, Mack, T, Marriott, M, Martinelli, V, Mason, D, McCauley, JL, Mentch, F, Mero, I-L, Mihalova, T, Montalban, X, Mottershead, J, Myhr, K-M, Naldi, P, Ollier, W, Page, A, Palotie, A, Pelletier, J, Piccio, L, Pickersgill, T, Piehl, F, Pobywajlo, S, Quach, HL, Ramsay, PP, Reunanen, M, Reynolds, R, Rioux, J, Rodegher, M, Roesner, S, Rubio, JP, Rueckert, I-M, Salvetti, M, Salvi, E, Santaniello, A, Schaefer, CA, Schreiber, S, Schulze, C, Scott, RJ, Sellebjerg, F, Selmaj, KW, Sexton, D, Shen, L, Simms-Acuna, B, Skidmore, S, Sleiman, PMA, Smestad, C, Sorensen, PS, Sondergaard, HB, Stankovich, J, Strange, RC, Sulonen, A-M, Sundqvist, E, Syvaenen, A-C, Taddeo, F, Taylor, B, Blackwell, JM, Tienari, P, Bramon, E, Tourbah, A, Brown, MA, Tronczynska, E, Casas, JP, Tubridy, N, Corvin, A, Vickery, J, Jankowski, J, Villoslada, P, Markus, HS, Wang, K, Mathew, CG, Wason, J, Palmer, CNA, Wichmann, H-E, Plomin, R, Willoughby, E, Rautanen, A, Winkelmann, J, Wittig, M, Trembath, RC, Yaouanq, J, Viswanathan, AC, Zhang, H, Wood, NW, Zuvich, R, Deloukas, P, Langford, C, Duncanson, A, Oksenberg, JR, Pericak-Vance, MA, Haines, JL, Olsson, T, Hillert, J, Ivinson, AJ, De Jager, PL, Peltonen, L, Stewart, GJ, Hafler, DA, Hauser, SL, McVean, G, Donnelly, P, Compston, A, Sawcer, S, Hellenthal, G, Pirinen, M, Spencer, CCA, Patsopoulos, NA, Moutsianas, L, Dilthey, A, Su, Z, Freeman, C, Hunt, SE, Edkins, S, Gray, E, Booth, DR, Potter, SC, Goris, A, Band, G, Oturai, AB, Strange, A, Saarela, J, Bellenguez, C, Fontaine, B, Gillman, M, Hemmer, B, Gwilliam, R, Zipp, F, Jayakumar, A, Martin, R, Leslie, S, Hawkins, S, Giannoulatou, E, D'alfonso, S, Blackburn, H, Boneschi, FM, Liddle, J, Harbo, HF, Perez, ML, Spurkland, A, Waller, MJ, Mycko, MP, Ricketts, M, Comabella, M, Hammond, N, Kockum, I, McCann, OT, Ban, M, Whittaker, P, Kemppinen, A, Weston, P, Hawkins, C, Widaa, S, Zajicek, J, Dronov, S, Robertson, N, Bumpstead, SJ, Barcellos, LF, Ravindrarajah, R, Abraham, R, Alfredsson, L, Ardlie, K, Aubin, C, Baker, A, Baker, K, Baranzini, SE, Bergamaschi, L, Bergamaschi, R, Bernstein, A, Berthele, A, Boggild, M, Bradfield, JP, Brassat, D, Broadley, SA, Buck, D, Butzkueven, H, Capra, R, Carroll, WM, Cavalla, P, Celius, EG, Cepok, S, Chiavacci, R, Clerget-Darpoux, F, Clysters, K, Comi, G, Cossburn, M, Cournu-Rebeix, I, Cox, MB, Cozen, W, Cree, BAC, Cross, AH, Cusi, D, Daly, MJ, Davis, E, de Bakker, PIW, Debouverie, M, D'hooghe, MB, Dixon, K, Dobosi, R, Dubois, B, Ellinghaus, D, Elovaara, I, Esposito, F, Fontenille, C, Foote, S, Franke, A, Galimberti, D, Ghezzi, A, Glessner, J, Gomez, R, Gout, O, Graham, C, Grant, SFA, Guerini, FR, Hakonarson, H, Hall, P, Hamsten, A, Hartung, H-P, Heard, RN, Heath, S, Hobart, J, Hoshi, M, Infante-Duarte, C, Ingram, G, Ingram, W, Islam, T, Jagodic, M, Kabesch, M, Kermode, AG, Kilpatrick, TJ, Kim, C, Klopp, N, Koivisto, K, Larsson, M, Lathrop, M, Lechner-Scott, JS, Leone, MA, Leppa, V, Liljedahl, U, Bomfim, IL, Lincoln, RR, Link, J, Liu, J, Lorentzen, AR, Lupoli, S, Macciardi, F, Mack, T, Marriott, M, Martinelli, V, Mason, D, McCauley, JL, Mentch, F, Mero, I-L, Mihalova, T, Montalban, X, Mottershead, J, Myhr, K-M, Naldi, P, Ollier, W, Page, A, Palotie, A, Pelletier, J, Piccio, L, Pickersgill, T, Piehl, F, Pobywajlo, S, Quach, HL, Ramsay, PP, Reunanen, M, Reynolds, R, Rioux, J, Rodegher, M, Roesner, S, Rubio, JP, Rueckert, I-M, Salvetti, M, Salvi, E, Santaniello, A, Schaefer, CA, Schreiber, S, Schulze, C, Scott, RJ, Sellebjerg, F, Selmaj, KW, Sexton, D, Shen, L, Simms-Acuna, B, Skidmore, S, Sleiman, PMA, Smestad, C, Sorensen, PS, Sondergaard, HB, Stankovich, J, Strange, RC, Sulonen, A-M, Sundqvist, E, Syvaenen, A-C, Taddeo, F, Taylor, B, Blackwell, JM, Tienari, P, Bramon, E, Tourbah, A, Brown, MA, Tronczynska, E, Casas, JP, Tubridy, N, Corvin, A, Vickery, J, Jankowski, J, Villoslada, P, Markus, HS, Wang, K, Mathew, CG, Wason, J, Palmer, CNA, Wichmann, H-E, Plomin, R, Willoughby, E, Rautanen, A, Winkelmann, J, Wittig, M, Trembath, RC, Yaouanq, J, Viswanathan, AC, Zhang, H, Wood, NW, Zuvich, R, Deloukas, P, Langford, C, Duncanson, A, Oksenberg, JR, Pericak-Vance, MA, Haines, JL, Olsson, T, Hillert, J, Ivinson, AJ, De Jager, PL, Peltonen, L, Stewart, GJ, Hafler, DA, Hauser, SL, McVean, G, Donnelly, P, and Compston, A
- Abstract
Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
- Published
- 2011
21. A kinetic isotope effect study and transition state analysis of the S-adenosylmethionine synthetase reaction.
- Author
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Markham, G.D., Parkin, D.W., Mentch, F., and Schramm, V.L.
- Abstract
The biosynthesis of S-adenosylmethionine occurs in a unique enzymatic reaction in which the synthesis of the sulfonium center results from displacement of the entire polyphosphate chain from MgATP. The mechanism of S-adenosylmethionine synthetase (ATP:L-methionine s-adenosyltransferase) from Escherichia coli has been characterized by kinetic isotope effect and substrate trapping measurements. Replacement of 12C by 14C at the 5′ carbon of ATP yields a primary Vmax/Km isotope effect (12C/14C) of 1.128 +/- 0.003 in the absence of added monovalent cation activator (K+). At saturating K+ concentrations (10 mM) the primary isotope effect diminishes slightly to 1.108 +/- 0.003, indicating that the step in the mechanism involving bond breaking at the 5′ carbon of MgATP has a small commitment to catalysis at conditions near Vmax. No alpha-secondary 3H isotope effect from [5′-3H]ATP was detected, (1H/3H) = 1.000 +/- 0.002, even in the absence of KCl. There was no significant primary sulfur isotope effect from [35S]methionine at KCl concentrations from 0 to 10 mM. Substitution of the methyl group of methionine with tritium yielded a beta-secondary isotope effect (CH3/C3H3) = 1.009 +/- 0.008 independent of KCl concentration. The reaction of selenomethionine and [5′-14C]ATP gave a primary isotope effect of 1.097 +/- 0.006, independent of KCl concentration. Substrate trapping experiments demonstrated that the step in the mechanism involving bond making to sulfur of methionine does not have a significant commitment to catalysis at 0.25 mM KCl, therefore intrinsic isotope effects were observed. Substrate trapping experiments indicated that the step involving bond breaking at carbon 5′ of MgATP has a 10% commitment to catalysis at 0.25 mM KCl. The isotope effects are interpreted in terms of an Sn2-like transition state structure in which bonding of the C5′ is symmetric with respect to the departing tripolyphosphate group and the incoming sulfur of methionine. With selenomethionine as substrate an earlier transition state is implicated.
- Published
- 1987
- Full Text
- View/download PDF
22. Ambient air pollution sensitivity and severity of pediatric asthma.
- Author
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Kelchtermans J, Mentch F, and Hakonarson H
- Subjects
- Humans, Child, Male, Female, Adolescent, Child, Preschool, Severity of Illness Index, Ozone analysis, Ozone adverse effects, Sulfur Dioxide analysis, Sulfur Dioxide adverse effects, Infant, Logistic Models, Asthma chemically induced, Air Pollution adverse effects, Air Pollution analysis, Air Pollutants analysis, Air Pollutants adverse effects, Particulate Matter analysis, Particulate Matter adverse effects, Environmental Exposure adverse effects, Environmental Exposure analysis
- Abstract
Background: Ambient air pollution exposure increases the incidence and severity of pediatric asthma. Despite this, we lack effective therapies to protect patients from the impact of ambient air pollution exposure. A roadblock is the inability to identify patients that are affected by air pollution., Objective: To examine the association between AAP sensitivity determined by individual exposure prior to asthma exacerbations and the severity of asthma in pediatric patients., Methods: We assess the association between spikes in ambient air pollution and asthma exacerbations. Patients were considered sensitive to a specific pollutant if they experienced an asthma exacerbation immediately following a spike in the concentration of that pollutant. Cut off values for these spikes were determined as two standard deviations above the mean concentration two weeks prior and two weeks post the days leading up to an asthma exacerbation., Results: We included 8129 pediatric patients with over 34,346 associated asthma exacerbations. In a multinomial log-linear logistic regression model comparing patients with mild asthma to patients with moderate or severe asthma, sensitivity to Ozone, SO
2 , PM2.5 and PM10 was significantly associated to severe as opposed to mild asthma (OR 1.39 with CI 1.08-1.78, 1.58 with CI 1.12-2.23, 1.37 with CI 1.07-1.76, and 1.63 with CI 1.12-2.37 respectively). Furthermore, moderate as opposed to mild asthma was significantly associated with sensitivity to SO2 and PM2.5 (OR 1.24 with CI 1.06-1.44 and 1.26 with CI 1.12-1.43, respectively)., Impact Statement: There is a subpopulation of pediatric asthma patients that experience asthma exacerbations just following spikes in ambient air pollution. This subgroup of patients has more severe asthma despite correction for significant confounders. The presented work is the first to reveal the clinically significant impact of variation in ambient air pollution sensitivity in pediatric asthma, highlighting the importance of accounting for variable sensitivity in the study of the effects of ambient air pollution exposure on pediatric asthma., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)- Published
- 2024
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23. Identification of genetic variants associated with clinical features of sickle cell disease.
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Tsukahara K, Chang X, Mentch F, Smith-Whitley K, Bhandari A, Norris C, Glessner JT, and Hakonarson H
- Subjects
- Humans, Male, Female, Adult, Phenotype, Genetic Predisposition to Disease, Adolescent, Fetal Hemoglobin genetics, Genotype, Acute Chest Syndrome genetics, Child, Young Adult, Genetic Variation, Anemia, Sickle Cell genetics, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Quantitative Trait Loci
- Abstract
Sickle cell disease (SCD) is an inherited blood disorder marked by homozygosity of hemoglobin S, which is a defective hemoglobin caused by a missense mutation in the β-globin gene. However, clinical phenotypes of SCD vary among patients. To investigate genetic variants associated with various clinical phenotypes of SCD, we genotyped DNA samples from 520 SCD subjects and used a genome-wide association study (GWAS) approach to identify genetic variants associated with phenotypic features of SCD. For HbF levels, the previously reported 2p16.1 locus (BCL11A) reached genome significance (rs1427407, P = 8.58 × 10
-10 ) in our GWAS as expected. In addition, we found a new genome-wide significance locus at 15q14 (rs8182015, P = 2.07 × 10-8 ) near gene EMC7. GWAS of acute chest syndrome (ACS) detected a locus (rs79915189, P = 3.70 × 10-8 ) near gene IDH2 at 15q26.1. The SNP, rs79915189, is also an expression quantitative trait locus (eQTL) of IDH2 in multiple tissues. For vasoocclusive episode (VOE), GWAS detected multiple significant signals at 2p25.1 (rs62118798, P = 4.27 × 10-8 ), 15q26.1 (rs62020555, P = 2.04 × 10-9 ) and 15q26.3 (rs117797325, P = 4.63 × 10-8 ). Our findings provide novel insights into the genetic mechanisms of SCD suggesting that common genetic variants play an important role in the presentation of the clinical phenotypes of patients with SCD., (© 2024. The Author(s).)- Published
- 2024
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24. Voriconazole metabolism is associated with the number of skin cancers per patient.
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Ike JI, Smith IT, Mosley D, Madden C, Grossarth S, Halle BR, Lewis A, Mentch F, Hakonarson H, Bastarache L, and Wheless L
- Subjects
- Humans, Retrospective Studies, Male, Female, Middle Aged, Aged, Organ Transplantation adverse effects, Adult, Voriconazole adverse effects, Skin Neoplasms epidemiology, Skin Neoplasms etiology, Skin Neoplasms metabolism, Antifungal Agents adverse effects, Carcinoma, Squamous Cell epidemiology, Carcinoma, Squamous Cell metabolism, Carcinoma, Squamous Cell etiology, Cytochrome P-450 CYP2C19 metabolism, Cytochrome P-450 CYP2C19 genetics
- Abstract
Voriconazole exposure is associated with skin cancer, but it is unknown how the full spectrum of its metabolizer phenotypes impacts this association. We conducted a retrospective cohort study to determine how variation in metabolism of voriconazole as measured by metabolizer status of CYP2C19 is associated with the total number of skin cancers a patient develops and the rate of development of the first skin cancer after treatment. There were 1,739 organ transplant recipients with data on CYP2C19 phenotype. Of these, 134 were exposed to voriconazole. There was a significant difference in the number of skin cancers after transplant based on exposure to voriconazole, metabolizer phenotype, and the interaction of these two (p < 0.01 for all three). This increase was driven primarily by number of squamous cell carcinomas among rapid metabolizes with voriconazole exposure (p < 0.01 for both). Patients exposed to voriconazole developed skin cancers more rapidly than those without exposure (Fine-Grey hazard ratio 1.78, 95% confidence interval 1.19-2.66). This association was similarly driven by development of SCC (Fine-Grey hazard ratio 1.83, 95% confidence interval 1.14-2.94). Differences in voriconazoles metabolism are associated with an increase in the number of skin cancers developed after transplant, particularly SCC., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
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- 2024
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25. GWAS reveals Genetic Susceptibility to Air Pollution-Related Asthma Exacerbations in Children of African Ancestry.
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Kelchtermans J, March ME, Mentch F, Liu Y, Nguyen K, and Hakonarson H
- Abstract
Background: The relationship between ambient air pollution (AAP) exposure and asthma exacerbations is well-established. However, mitigation efforts have yielded mixed results, potentially due to genetic variability in the response to AAP. We hypothesize that common single nucleotide polymorphisms (SNPs) are linked to AAP sensitivity and test this through a Genome Wide Association Study (GWAS)., Methods: We selected a cohort of pediatric asthma patients frequently exposed to AAP. Patients experiencing exacerbations immediately following AAP spikes were deemed sensitive. A GWAS compared sensitive versus non-sensitive patients. Findings were validated using data from the All of Us program., Results: Our study included 6,023 pediatric asthma patients. Due to the association between AAP exposure and race, GWAS analysis was feasible only in the African ancestry cohort. Seven risk loci reached genome-wide significance, including four non-intergenic variants. Two variants were validated: rs111970601 associated with sensitivity to CO (odds ratio [OR], 6.58; PL=L1.63L×L10-8; 95% CI, 3.42-12.66) and rs9836522 to PM2.5 sensitivity (OR 0.75; PL=L3,87 ×L10-9; 95% CI, 0.62-0.91)., Interpretation: While genetic variants have been previously linked to asthma incidence and AAP exposure, this study is the first to link specific SNPs with AAP-related asthma exacerbations. The identified variants implicate genes with a known role in asthma and established links to AAP. Future research should explore how clinical interventions interact with genetic risk to mitigate the effects of AAP, particularly to enhance health equity for vulnerable populations., What Is Already Known on This Topic: The relationship between ambient air pollution (AAP) exposure and asthma exacerbations is well-established. However, efforts to mitigate the impact of AAP on children with asthma have yielded mixed results, potentially due to genetic variability in response to AAP., What This Study Adds: Using publicly available AAP data, we identify which children with asthma experience exacerbations immediately following spikes in AAP. We then conduct a Genome Wide Association Study (GWAS) comparing these patients with those who have no temporal association between AAP spikes and asthma exacerbations, identifying several Single Nucleotide Polymorphisms (SNPs) significantly associated with AAP sensitivity., How This Study Might Affect Research Practice or Policy: While genetic variants have previously been linked to asthma incidence and AAP exposure, this study is the first to link specific SNPs with AAP-related asthma exacerbations. This creates a framework for identifying children especially at risk when exposed to AAP. These children should be targeted with policy interventions to reduce exposure and may require specific treatments to mitigate the effects of ongoing AAP exposure in the interim.
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- 2024
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26. Trans-ethnic genomic informed risk assessment for Alzheimer's disease: An International Hundred K+ Cohorts Consortium study.
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Sleiman PM, Qu HQ, Connolly JJ, Mentch F, Pereira A, Lotufo PA, Tollman S, Choudhury A, Ramsay M, Kato N, Ozaki K, Mitsumori R, Jeon JP, Hong CH, Son SJ, Roh HW, Lee DG, Mukadam N, Foote IF, Marshall CR, Butterworth A, Prins BP, Glessner JT, and Hakonarson H
- Subjects
- Humans, Female, Genome-Wide Association Study, Proteomics, Genomics, Risk Assessment, Alzheimer Disease genetics, Alzheimer Disease epidemiology
- Abstract
Background: As a collaboration model between the International HundredK+ Cohorts Consortium (IHCC) and the Davos Alzheimer's Collaborative (DAC), our aim was to develop a trans-ethnic genomic informed risk assessment (GIRA) algorithm for Alzheimer's disease (AD)., Methods: The GIRA model was created to include polygenic risk score calculated from the AD genome-wide association study loci, the apolipoprotein E haplotypes, and non-genetic covariates including age, sex, and the first three principal components of population substructure., Results: We validated the performance of the GIRA model in different populations. The proteomic study in the participant sites identified proteins related to female infertility and autoimmune thyroiditis and associated with the risk scores of AD., Conclusions: As the initial effort by the IHCC to leverage existing large-scale datasets in a collaborative setting with DAC, we developed a trans-ethnic GIRA for AD with the potential of identifying individuals at high risk of developing AD for future clinical applications., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)
- Published
- 2023
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27. Trans-ethnic polygenic risk scores for body mass index: An international hundred K+ cohorts consortium study.
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Qu HQ, Connolly JJ, Kraft P, Long J, Pereira A, Flatley C, Turman C, Prins B, Mentch F, Lotufo PA, Magnus P, Stampfer MJ, Tamimi R, Eliassen AH, Zheng W, Knudsen GPS, Helgeland O, Butterworth AS, Hakonarson H, and Sleiman PM
- Subjects
- Child, Humans, Bayes Theorem, Body Mass Index, Risk Factors, Genome-Wide Association Study, Multifactorial Inheritance genetics
- Abstract
Background: While polygenic risk scores hold significant promise in estimating an individual's risk of developing a complex trait such as obesity, their application in the clinic has, to date, been limited by a lack of data from non-European populations. As a collaboration model of the International Hundred K+ Cohorts Consortium (IHCC), we endeavored to develop a globally applicable trans-ethnic PRS for body mass index (BMI) through this relatively new international effort., Methods: The polygenic risk score (PRS) model was developed, trained and tested at the Center for Applied Genomics (CAG) of The Children's Hospital of Philadelphia (CHOP) based on a BMI meta-analysis from the GIANT consortium. The validated PRS models were subsequently disseminated to the participating sites. Scores were generated by each site locally on their cohorts and summary statistics returned to CAG for final analysis., Results: We show that in the absence of a well powered trans-ethnic GWAS from which to derive marker SNPs and effect estimates for PRS, trans-ethnic scores can be generated from European ancestry GWAS using Bayesian approaches such as LDpred, by adjusting the summary statistics using trans-ethnic linkage disequilibrium reference panels. The ported trans-ethnic scores outperform population specific-PRS across all non-European ancestry populations investigated including East Asians and three-way admixed Brazilian cohort., Conclusions: Here we show that for a truly polygenic trait such as BMI adjusting the summary statistics of a well powered European ancestry study using trans-ethnic LD reference results in a score that is predictive across a range of ancestries including East Asians and three-way admixed Brazilians., (© 2023 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)
- Published
- 2023
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28. Rare recurrent copy number variations in metabotropic glutamate receptor interacting genes in children with neurodevelopmental disorders.
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Glessner JT, Khan ME, Chang X, Liu Y, Otieno FG, Lemma M, Slaby I, Hain H, Mentch F, Li J, Kao C, Sleiman PMA, March ME, Connolly J, and Hakonarson H
- Subjects
- Humans, DNA Copy Number Variations genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Autism Spectrum Disorder genetics, Receptors, Metabotropic Glutamate genetics
- Abstract
Background: Neurodevelopmental disorders (NDDs), such as attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), are examples of complex and partially overlapping phenotypes that often lack definitive corroborating genetic information. ADHD and ASD have complex genetic associations implicated by rare recurrent copy number variations (CNVs). Both of these NDDs have been shown to share similar biological etiologies as well as genetic pleiotropy., Methods: Platforms aimed at investigating genetic-based associations, such as high-density microarray technologies, have been groundbreaking techniques in the field of complex diseases, aimed at elucidating the underlying disease biology. Previous studies have uncovered CNVs associated with genes within shared candidate genomic networks, including glutamate receptor genes, across multiple different NDDs. To examine shared biological pathways across two of the most common NDDs, we investigated CNVs across 15,689 individuals with ADHD (n = 7920), ASD (n = 4318), or both (n = 3,416), as well as 19,993 controls. Cases and controls were matched by genotype array (i.e., Illumina array versions). Three case-control association studies each calculated and compared the observed vs. expected frequency of CNVs across individual genes, loci, pathways, and gene networks. Quality control measures of confidence in CNV-calling, prior to association analyses, included visual inspection of genotype and hybridization intensity., Results: Here, we report results from CNV analysis in search for individual genes, loci, pathways, and gene networks. To extend our previous observations implicating a key role of the metabotropic glutamate receptor (mGluR) network in both ADHD and autism, we exhaustively queried patients with ASD and/or ADHD for CNVs associated with the 273 genomic regions of interest within the mGluR gene network (genes with one or two degrees protein-protein interaction with mGluR 1-8 genes). Among CNVs in mGluR network genes, we uncovered CNTN4 deletions enriched in NDD cases (P = 3.22E - 26, OR = 2.49). Additionally, we uncovered PRLHR deletions in 40 ADHD cases and 12 controls (P = 5.26E - 13, OR = 8.45) as well as clinically diagnostic relevant 22q11.2 duplications and 16p11.2 duplications in 23 ADHD + ASD cases and 9 controls (P = 4.08E - 13, OR = 15.05) and 22q11.2 duplications in 34 ADHD + ASD cases and 51 controls (P = 9.21E - 9, OR = 3.93); those control samples were not with previous 22qDS diagnosis in their EHR records., Conclusion: Together, these results suggest that disruption in neuronal cell-adhesion pathways confers significant risk to NDDs and showcase that rare recurrent CNVs in CNTN4, 22q11.2, and 16p11.2 are overrepresented in NDDs that constitute patients predominantly suffering from ADHD and ASD., Trial Registration: ClinicalTrials.gov Identifier: NCT02286817 First Posted: 10 November 14, ClinicalTrials.gov Identifier: NCT02777931 first posted: 19 May 2016, ClinicalTrials.gov Identifier: NCT03006367 first posted: 30 December 2016, ClinicalTrials.gov Identifier: NCT02895906 first posted: 12 September 2016., (© 2023. The Author(s).)
- Published
- 2023
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29. Genetic architecture of asthma in African American patients.
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Chang X, March M, Mentch F, Qu H, Liu Y, Glessner J, Sleiman P, and Hakonarson H
- Subjects
- Child, Humans, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Proteins genetics, Quantitative Trait Loci, Short Chain Dehydrogenase-Reductases genetics, Asthma genetics, Black or African American genetics
- Abstract
Background: Asthma is a chronic inflammatory disorder with a strong genetic inheritance. Although more than 100 loci were reported through the genome-wide association study of European populations, the genetic underpinning of asthma in African American individuals remains largely elusive., Objective: We aimed to identify genetic loci associated with asthma in African American individuals., Methods: Three cohorts were genotyped at the Children's Hospital of Philadelphia by using the Illumina single-nucleotide polymorphism array platform. Genotype imputation was performed by using the Trans-Omics for Precision Medicine (TOPMed) reference panel, which includes whole genome sequencing data from more than 100,000 individuals. A meta-analysis of 3 Children's Hospital of Philadelphia cohorts and 10 Consortium on Asthma among African Ancestry Populations in the Americas cohorts, totaling 19,628 subjects, was conducted to identify genetic loci associated with asthma in African American individuals., Results: Our study identified 12 loci surpassing the classical genome-wide significance threshold (5 × 10
-8 ). Of those loci, 8 reached the stricter significance threshold (3 × 10-8 ). The 9p24.1 locus (rs10975467 [P = 1.63 × 10-8 ]) has previously been associated with asthma in European individuals. Six loci are associated with enhancer activities, 2 loci are in DNase I-hypersensitive regions, and all of them are associated with regulatory motifs. Moreover, the locus 11q13.4 (rs7480008) is an expression quantitative trait locus of XRRA1 in lung (P = 9.4 × 10-10 ), and the locus 13q14.3 (rs1543525) is a splicing quantitative trait locus of DHRS12 in lung (P = 1.1 × 10-13 )., Conclusions: Our findings provide candidate genetic loci for therapeutic target identification and prioritization for African populations., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)- Published
- 2023
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30. Returning integrated genomic risk and clinical recommendations: The eMERGE study.
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Linder JE, Allworth A, Bland HT, Caraballo PJ, Chisholm RL, Clayton EW, Crosslin DR, Dikilitas O, DiVietro A, Esplin ED, Forman S, Freimuth RR, Gordon AS, Green R, Harden MV, Holm IA, Jarvik GP, Karlson EW, Labrecque S, Lennon NJ, Limdi NA, Mittendorf KF, Murphy SN, Orlando L, Prows CA, Rasmussen LV, Rasmussen-Torvik L, Rowley R, Sawicki KT, Schmidlen T, Terek S, Veenstra D, Velez Edwards DR, Absher D, Abul-Husn NS, Alsip J, Bangash H, Beasley M, Below JE, Berner ES, Booth J, Chung WK, Cimino JJ, Connolly J, Davis P, Devine B, Fullerton SM, Guiducci C, Habrat ML, Hain H, Hakonarson H, Harr M, Haverfield E, Hernandez V, Hoell C, Horike-Pyne M, Hripcsak G, Irvin MR, Kachulis C, Karavite D, Kenny EE, Khan A, Kiryluk K, Korf B, Kottyan L, Kullo IJ, Larkin K, Liu C, Malolepsza E, Manolio TA, May T, McNally EM, Mentch F, Miller A, Mooney SD, Murali P, Mutai B, Muthu N, Namjou B, Perez EF, Puckelwartz MJ, Rakhra-Burris T, Roden DM, Rosenthal EA, Saadatagah S, Sabatello M, Schaid DJ, Schultz B, Seabolt L, Shaibi GQ, Sharp RR, Shirts B, Smith ME, Smoller JW, Sterling R, Suckiel SA, Thayer J, Tiwari HK, Trinidad SB, Walunas T, Wei WQ, Wells QS, Weng C, Wiesner GL, Wiley K, and Peterson JF
- Subjects
- Humans, Prospective Studies, Risk Factors, Risk Assessment, Genome, Genomics methods
- Abstract
Purpose: Assessing the risk of common, complex diseases requires consideration of clinical risk factors as well as monogenic and polygenic risks, which in turn may be reflected in family history. Returning risks to individuals and providers may influence preventive care or use of prophylactic therapies for those individuals at high genetic risk., Methods: To enable integrated genetic risk assessment, the eMERGE (electronic MEdical Records and GEnomics) network is enrolling 25,000 diverse individuals in a prospective cohort study across 10 sites. The network developed methods to return cross-ancestry polygenic risk scores, monogenic risks, family history, and clinical risk assessments via a genome-informed risk assessment (GIRA) report and will assess uptake of care recommendations after return of results., Results: GIRAs include summary care recommendations for 11 conditions, education pages, and clinical laboratory reports. The return of high-risk GIRA to individuals and providers includes guidelines for care and lifestyle recommendations. Assembling the GIRA required infrastructure and workflows for ingesting and presenting content from multiple sources. Recruitment began in February 2022., Conclusion: Return of a novel report for communicating monogenic, polygenic, and family history-based risk factors will inform the benefits of integrated genetic risk assessment for routine health care., Competing Interests: Conflict of Interest N.S.A.-H. is an employee and equity holder of 23andMe; serves as a scientific advisory board member for Allelica, Inc; received personal fees from Genentech Inc, Allelica Inc, and 23andMe; received research funding from Akcea Therapeutics; and was previously employed by Regeneron Pharmaceuticals. T.W. has grant funding from Gilead Sciences, Inc. L.O. and T.R.-B are founders of a company developing MeTree. T.S., E.D.E., and E.H. are employees and stockholders of Invitae Corporation. E.M.M. has been a consultant for Avidity Bioscience, Amgen Inc, AstraZeneca, Cytokinetics, Invitae Corporation, Janssen Pharmaceuticals, Pfizer Inc, PepGen Inc, Tenaya Therapeutics, and Stealth BioTherapeutics Inc; she is also the founder of Ikaika Therapeutics. E.E.K. received personal fees from Illumina Inc, 23andMe, and Regeneron Pharmaceuticals and serves as a scientific advisory board member for Encompass Bioscience, Foresite Labs, and Galateo Bio. B.K. is an advisory board member and stockholder of Genome Medical. M.S. is a member of the Institutional Review Board of the All of Us Research Program. E.F.P. is a paid consultant for Allecia Inc. J.F.P. is a paid consultant for Natera Inc. All other authors declare no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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31. Evaluation of the portability of computable phenotypes with natural language processing in the eMERGE network.
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Pacheco JA, Rasmussen LV, Wiley K Jr, Person TN, Cronkite DJ, Sohn S, Murphy S, Gundelach JH, Gainer V, Castro VM, Liu C, Mentch F, Lingren T, Sundaresan AS, Eickelberg G, Willis V, Furmanchuk A, Patel R, Carrell DS, Deng Y, Walton N, Satterfield BA, Kullo IJ, Dikilitas O, Smith JC, Peterson JF, Shang N, Kiryluk K, Ni Y, Li Y, Nadkarni GN, Rosenthal EA, Walunas TL, Williams MS, Karlson EW, Linder JE, Luo Y, Weng C, and Wei W
- Subjects
- Genomics, Algorithms, Phenotype, Electronic Health Records, Natural Language Processing
- Abstract
The electronic Medical Records and Genomics (eMERGE) Network assessed the feasibility of deploying portable phenotype rule-based algorithms with natural language processing (NLP) components added to improve performance of existing algorithms using electronic health records (EHRs). Based on scientific merit and predicted difficulty, eMERGE selected six existing phenotypes to enhance with NLP. We assessed performance, portability, and ease of use. We summarized lessons learned by: (1) challenges; (2) best practices to address challenges based on existing evidence and/or eMERGE experience; and (3) opportunities for future research. Adding NLP resulted in improved, or the same, precision and/or recall for all but one algorithm. Portability, phenotyping workflow/process, and technology were major themes. With NLP, development and validation took longer. Besides portability of NLP technology and algorithm replicability, factors to ensure success include privacy protection, technical infrastructure setup, intellectual property agreement, and efficient communication. Workflow improvements can improve communication and reduce implementation time. NLP performance varied mainly due to clinical document heterogeneity; therefore, we suggest using semi-structured notes, comprehensive documentation, and customization options. NLP portability is possible with improved phenotype algorithm performance, but careful planning and architecture of the algorithms is essential to support local customizations., (© 2023. The Author(s).)
- Published
- 2023
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32. Trans-ethnic Polygenic Risk Scores for Body Mass Index: An International Hundred K+ Cohorts Consortium Study.
- Author
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Qu H, Connolly JJ, Kraft P, Long J, Pereira A, Flatley C, Turman C, Prins B, Mentch F, Lotufo PA, Magnus P, Stampfer MJ, Tamimi R, Eliassen AH, Zheng W, Knudsen GPS, Helgeland O, Butterworth AS, Hakonarson H, and Sleiman PM
- Abstract
Background: While polygenic risk scores hold significant promise in estimating an individual's risk of developing a complex trait such as obesity, their application in the clinic has, to date, been limited by a lack of data from non-European populations. As a collaboration model of the International Hundred K+ Cohorts Consortium (IHCC), we endeavored to develop a globally applicable trans-ethnic PRS for body mass index (BMI) through this relatively new international effort., Methods: The PRS model was developed trained and tested at the Center for Applied Genomics (CAG) of The Children's Hospital of Philadelphia (CHOP) based on a BMI meta-analysis from the GIANT consortium. The validated PRS models were subsequently disseminated to the participating sites. Scores were generated by each site locally on their cohorts and summary statistics returned to CAG for final analysis., Results: We show that in the absence of a well powered trans-ethnic GWAS from which to derive SNPs and effect estimates, trans-ethnic scores can be generated from European ancestry GWAS using Bayesian approaches such as LDpred to adjust the summary statistics using trans-ethnic linkage disequilibrium reference panels. The ported trans-ethnic scores outperform population specific-PRS across all non-European ancestry populations investigated including East Asians and three-way admixed Brazilian cohort., Conclusions: Widespread use of PRS in the clinic is hampered by a lack of genotyping data in individuals of non-European ancestry for the vast majority of traits. Here we show that for a truly polygenic trait such as BMI adjusting the summary statistics of a well powered European ancestry study using trans-ethnic LD reference results in a score that is predictive across a range of ancestries including East Asians and three-way admixed Brazilians.
- Published
- 2023
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33. Molecular diagnosis and novel genes and phenotypes in a pediatric thoracic insufficiency cohort.
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Strong A, Behr M, Lott C, Clark AJ, Mentch F, Da Silva RP, Rux DR, Campbell R, Skraban C, Wang X, Anari JB, Sinder B, Cahill PJ, Sleiman P, and Hakonarson H
- Subjects
- Phenotype, Spine
- Abstract
Thoracic insufficiency syndromes are a genetically and phenotypically heterogeneous group of disorders characterized by congenital abnormalities or progressive deformation of the chest wall and/or vertebrae that result in restrictive lung disease and compromised respiratory capacity. We performed whole exome sequencing on a cohort of 42 children with thoracic insufficiency to elucidate the underlying molecular etiologies of syndromic and non-syndromic thoracic insufficiency and predict extra-skeletal manifestations and disease progression. Molecular diagnosis was established in 24/42 probands (57%), with 18/24 (75%) probands having definitive diagnoses as defined by laboratory and clinical criteria and 6/24 (25%) probands having strong candidate genes. Gene identified in cohort patients most commonly encoded components of the primary cilium, connective tissue, and extracellular matrix. A novel association between KIF7 and USP9X variants and thoracic insufficiency was identified. We report and expand the genetic and phenotypic spectrum of a cohort of children with thoracic insufficiency, reinforce the prevalence of extra-skeletal manifestations in thoracic insufficiency syndromes, and expand the phenotype of KIF7 and USP9X-related disease to include thoracic insufficiency., (© 2023. The Author(s).)
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- 2023
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34. Metabolomic profiling for dyslipidemia in pediatric patients with sickle cell disease, on behalf of the IHCC consortium.
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Qu HQ, Glessner J, Qu J, Mentch F, Campbell I, Sleiman P, Connolly JJ, and Hakonarson H
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- Humans, Child, Metabolomics, Plasma, Triglycerides, Dyslipidemias, Anemia, Sickle Cell complications
- Abstract
Background: Previous study has shown that dyslipidemia is common in patients with Sickle cell disease (SCD) and is associated with more serious SCD complications., Methods: This study investigated systematically dyslipidemia in SCD using a state-of-art nuclear magnetic resonance (NMR) metabolomics platform, including 147 pediatric cases with SCD and 1234 controls without SCD. We examined 249 metabolomic biomarkers, including 98 biomarkers for lipoprotein subclasses, 70 biomarkers for relative lipoprotein lipid concentrations, plus biomarkers for fatty acids and phospholipids., Results: Specific patterns of hypolipoproteinemia and hypocholesterolemia in pediatric SCD were observed in lipoprotein subclasses other than larger VLDL subclasses. Triglycerides are not significantly changed in SCD, except increased relative concentrations in lipoprotein subclasses. Decreased plasma FFAs (including total-FA, SFA, PUFA, Omega-6, and linoleic acid) and decreased plasma phospholipids were observed in SCD., Conclusion: This study scrutinized, for the first time, lipoprotein subclasses in pediatric patients with SCD, and identified SCD-specific dyslipidemia from altered lipoprotein metabolism. The findings of this study depict a broad panorama of lipid metabolism and nutrition in SCD, suggesting the potential of specific dietary supplementation of the deficient nutrients for the management of SCD., (© 2022. The Author(s).)
- Published
- 2022
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35. Quantifying the phenome-wide disease burden of obesity using electronic health records and genomics.
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Robinson JR, Carroll RJ, Bastarache L, Chen Q, Pirruccello J, Mou Z, Wei WQ, Connolly J, Mentch F, Crane PK, Hebbring SJ, Crosslin DR, Gordon AS, Rosenthal EA, Stanaway IB, Hayes MG, Wei W, Petukhova L, Namjou-Khales B, Zhang G, Safarova MS, Walton NA, Still C, Bottinger EP, Loos RJF, Murphy SN, Jackson GP, Abumrad N, Kullo IJ, Jarvik GP, Larson EB, Weng C, Roden D, Khera AV, and Denny JC
- Subjects
- Humans, Electronic Health Records, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Genomics, Genetic Predisposition to Disease, Obesity epidemiology, Obesity genetics, Phenotype, Cost of Illness, Phenomics, Diabetes Mellitus, Type 2 epidemiology, Diabetes Mellitus, Type 2 genetics
- Abstract
Objective: High BMI is associated with many comorbidities and mortality. This study aimed to elucidate the overall clinical risk of obesity using a genome- and phenome-wide approach., Methods: This study performed a phenome-wide association study of BMI using a clinical cohort of 736,726 adults. This was followed by genetic association studies using two separate cohorts: one consisting of 65,174 adults in the Electronic Medical Records and Genomics (eMERGE) Network and another with 405,432 participants in the UK Biobank., Results: Class 3 obesity was associated with 433 phenotypes, representing 59.3% of all billing codes in individuals with severe obesity. A genome-wide polygenic risk score for BMI, accounting for 7.5% of variance in BMI, was associated with 296 clinical diseases, including strong associations with type 2 diabetes, sleep apnea, hypertension, and chronic liver disease. In all three cohorts, 199 phenotypes were associated with class 3 obesity and polygenic risk for obesity, including novel associations such as increased risk of renal failure, venous insufficiency, and gastroesophageal reflux., Conclusions: This combined genomic and phenomic systematic approach demonstrated that obesity has a strong genetic predisposition and is associated with a considerable burden of disease across all disease classes., (© 2022 The Obesity Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)
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- 2022
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36. COVID-19 in pediatrics: Genetic susceptibility.
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Glessner JT, Chang X, Mentch F, Qu H, Abrams DJ, Thomas A, Sleiman PMA, and Hakonarson H
- Abstract
The uptick in SARS-CoV-2 infection has resulted in a worldwide COVID-19 pandemic, which has created troublesome health and economic problems. We performed case-control meta-analyses in both African and European ethnicity COVID-19 disease cases based on laboratory test and phenotypic criteria. The cases had laboratory-confirmed SARS-CoV-2 infection. We uniquely investigated COVID infection genetics in a pediatric population. Our cohort has a large African ancestry component, also unique to our study. We tested for genetic variant association in 498 cases vs. 1,533 controls of African ancestry and 271 cases vs. 855 controls of European ancestry. We acknowledge that the sample size is relatively small, owing to the low prevalence of COVID infection among pediatric individuals. COVID-19 cases averaged 13 years of age. Pediatric genetic studies enhance the ability to detect genetic associations with a limited possible environment impact. Our findings support the notion that some genetic variants, most notably at the SEMA6D, FMN1, ACTN1, PDS5B, NFIA, ADGRL3, MMP27, TENM3, SPRY4, MNS1, and RSU1 loci, play a role in COVID-19 infection susceptibility. The pediatric cohort also shows nominal replication of previously reported adult study results: CCR9, CXCR6, FYCO1, LZTFL1, TDGF1, CCR1, CCR2, CCR3, CCR5, MAPT-AS1, and IFNAR2 gene variants. Reviewing the biological roles of genes implicated here, NFIA looks to be the most interesting as it binds to a palindromic sequence observed in both viral and cellular promoters and in the adenovirus type 2 origin of replication., 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 © 2022 Glessner, Chang, Mentch, Qu, Abrams, Thomas, Sleiman and Hakonarson.)
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- 2022
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37. Genetic analysis for type 1 diabetes genes in juvenile dermatomyositis unveils genetic disease overlap.
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Qu HQ, Qu J, Vaccaro C, Chang X, Mentch F, Li J, Mafra F, Nguyen K, Gonzalez M, March M, Pellegrino R, Glessner J, Sleiman P, Kao C, and Hakonarson H
- Subjects
- Genetic Predisposition to Disease, Genetic Testing, Humans, Autoimmune Diseases genetics, Dermatomyositis genetics, Diabetes Mellitus, Type 1 genetics
- Abstract
Objectives: JDM is a serious autoimmune and complex genetic disease. Another autoimmune genetic disease, type 1 diabetes (T1D), has been observed for significantly increased prevalence in families with JDM, while increased JDM risk has also been observed in T1D cases. This study aimed to study whether these two autoimmune diseases, JDM and T1D, share common genetic susceptibility., Methods: From 169 JDM families, 121 unrelated cases with European ancestry (EA) were identified by genome-wide genotyping, principal component analysis and identical-by-descent (IBD) analysis. T1D genetic risk score (GRS) were calculated in these cases and were compared with 361 EA T1D cases and 1943 non-diabetes EA controls. A total of 113 cases of the 121 unrelated European cases were sequenced by whole exome sequencing., Results: We observed increased T1D GRS in JDM cases (P = 9.42E-05). Using whole exome sequencing, we uncovered the T1D genes, phospholipase B1, cystic fibrosis transmembrane conductance regulator, tyrosine hydroxylase, CD6 molecule, perforin 1 and dynein axonemal heavy chain 2, potentially associated with JDM by the burden test of rare functional coding variants., Conclusion: Novel mechanisms of JDM related to these T1D genes are suggested by this study, which may imply novel therapeutic targets for JDM and warrant further study., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
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- 2022
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38. Metabolomic profiling of samples from pediatric patients with asthma unveils deficient nutrients in African Americans.
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Qu HQ, Glessner J, Qu J, Gilhool S, Mentch F, Campbell I, Sleiman P, Connolly JJ, and Hakonarson H
- Abstract
Plasma metabolomics represents a potentially powerful approach to understand the biochemical mechanisms of nutrition and metabolism in asthma. This study aims to acquire knowledge on plasma metabolites in asthma, which may provide avenues for nutrition therapy, as well as explanations for the observed effects in existing therapies. This study investigated 249 metabolites from 18 metabolite groups in a large cohort of African American population, including 602 pediatric patients with asthma and 593 controls, using a nuclear magnetic resonance (NMR) metabolomics platform. Decreased levels of citrate, ketone bodies, and two amino acids histidine (His) and glutamine (Gln), were observed in asthma cases compared to controls. Metabolites for lipid metabolism lost significance after controlling for comorbid obesity. For the first time, this study depicts a broad panorama of lipid metabolism and nutrition in asthma. Supplementation or augmentation of nutrients that are deficient may be beneficial for asthma care., Competing Interests: The authors declare no competing interests., (© 2022 The Authors.)
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- 2022
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39. Improved genetic risk scoring algorithm for type 1 diabetes prediction.
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Qu HQ, Qu J, Glessner J, Liu Y, Mentch F, Chang X, March M, Li J, Roizen JD, Connolly JJ, Sleiman P, and Hakonarson H
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- Algorithms, Child, Genetic Markers, Genetic Predisposition to Disease, Humans, Polymorphism, Single Nucleotide, Risk Factors, Diabetes Mellitus, Type 1 diagnosis, Diabetes Mellitus, Type 1 epidemiology, Diabetes Mellitus, Type 1 genetics
- Abstract
Background: Precise risk prediction of type 1 diabetes (T1D) facilitates early intervention and identification of risk factors prior to irreversible beta-islet cell destruction, and can significantly improve T1D prevention and clinical care. Sharp et al. developed a genetic risk scoring (GRS) system for T1D (T1D-GRS2) capable of predicting T1D risk in children of European ancestry. The T1D-GRS2 was developed on the basis of causal genetic variants, thus may be applicable to minor populations, while a trans-ethnic GRS for T1D may avoid the exacerbation of health disparities due to the lack of genomic information in minorities., Methods: Here, we describe a T1D-GRS2 calculator validated in two independent cohorts, including African American children and European American children. Participants were recruited by the Center for Applied Genomics at the Children's Hospital of Philadelphia., Results: It demonstrates that GRS2 is applicable to the T1D risk prediction in the AA cohort, while population-specific thresholds are needed for different populations., Conclusions: The study highlights the potential to further improve T1D-GRS2 performance with the inclusion of additional genetic markers., (© 2022 John Wiley & Sons A/S . Published by John Wiley & Sons Ltd.)
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- 2022
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40. A genome-wide association meta-analysis identifies new eosinophilic esophagitis loci.
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Chang X, March M, Mentch F, Nguyen K, Glessner J, Qu H, Liu Y, Furuta G, Aceves S, Gonsalves N, Nadeau K, Cianferoni A, Spergel J, Sleiman P, and Hakonarson H
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- Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Polymorphism, Single Nucleotide, Eosinophilic Esophagitis genetics
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Background: Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder of the esophagus marked by eosinophilic infiltration. Cumulative evidence indicates that the risk of EoE involves the complex interplay of both genetic and environmental factors. Because only a few genetic loci have been identified in EoE, the genetic underpinning of EoE remains largely elusive., Objective: We sought to identify genetic loci associated with EoE., Methods: Four EoE cohorts were genotyped using the Illumina single nucleotide polymorphism array platform, totaling 1,930 cases and 13,634 controls of European ancestry. Genotype imputation was performed with the Michigan Imputation Server using the Trans-Omics for Precision Medicine reference panel including whole-genome sequencing data from more than 100,000 individuals. Meta-analysis was conducted to identify potential novel genetic loci associated with EoE., Results: Our study identified 11 new genome-wide significant loci, of which 6 are common variant loci, including 5q31.1 (rs2106984, P = 4.16 × 10
-8 ; odds ratio [OR], 1.26, RAD50), 15q22.2 (rs2279293, P = 1.23 × 10-10 ; OR, 0.69, RORA), and 15q23 (rs56062135, P = 2.91 × 10-11 ; OR, 1.29, SMAD3), which have been previously associated with allergic conditions. Interestingly, a low-frequency synonymous mutation within the MATN2 gene was identified as the most significant single nucleotide polymorphism at the 8q22.1 locus. We also identified 5 sex-specific loci in the EoE cases, including an inflammatory bowel disease-associated locus at 9p24.1 (rs62541556, P = 4.4 × 10-8 ; OR, 1.11, JAK2)., Conclusions: Our findings demonstrate shared genetic underpinnings between EoE and other immune-mediated diseases and provide novel candidate genes for therapeutic target identification and prioritization., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)- Published
- 2022
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41. Under-specification as the source of ambiguity and vagueness in narrative phenotype algorithm definitions.
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Yu J, Pacheco JA, Ghosh AS, Luo Y, Weng C, Shang N, Benoit B, Carrell DS, Carroll RJ, Dikilitas O, Freimuth RR, Gainer VS, Hakonarson H, Hripcsak G, Kullo IJ, Mentch F, Murphy SN, Peissig PL, Ramirez AH, Walton N, Wei WQ, and Rasmussen LV
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- Genomics, Humans, Knowledge Bases, Phenotype, Algorithms, Electronic Health Records
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Introduction: Currently, one of the commonly used methods for disseminating electronic health record (EHR)-based phenotype algorithms is providing a narrative description of the algorithm logic, often accompanied by flowcharts. A challenge with this mode of dissemination is the potential for under-specification in the algorithm definition, which leads to ambiguity and vagueness., Methods: This study examines incidents of under-specification that occurred during the implementation of 34 narrative phenotyping algorithms in the electronic Medical Record and Genomics (eMERGE) network. We reviewed the online communication history between algorithm developers and implementers within the Phenotype Knowledge Base (PheKB) platform, where questions could be raised and answered regarding the intended implementation of a phenotype algorithm., Results: We developed a taxonomy of under-specification categories via an iterative review process between two groups of annotators. Under-specifications that lead to ambiguity and vagueness were consistently found across narrative phenotype algorithms developed by all involved eMERGE sites., Discussion and Conclusion: Our findings highlight that under-specification is an impediment to the accuracy and efficiency of the implementation of current narrative phenotyping algorithms, and we propose approaches for mitigating these issues and improved methods for disseminating EHR phenotyping algorithms., (© 2022. The Author(s).)
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- 2022
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42. Genetic association of primary nonresponse to anti-TNFα therapy in patients with inflammatory bowel disease.
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De T, Zhang H, Alarcon C, Lec B, Avitia J, Smithberger E, Chen C, Horvath M, Kwan S, Young M, Adhikari S, Kwon J, Pacheco J, Jarvik G, Wei WQ, Mentch F, Hakonarson H, Sleiman P, Gordon A, Harley J, Linneman J, Hebbring S, Parisiadou L, and Perera MA
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- Case-Control Studies, Cohort Studies, Humans, Tumor Necrosis Factor-alpha genetics, Genome-Wide Association Study, Inflammatory Bowel Diseases drug therapy, Inflammatory Bowel Diseases genetics
- Abstract
Objectives: Primary nonresponse (PNR) to antitumor necrosis factor-α (TNFα) biologics is a serious concern in patients with inflammatory bowel disease (IBD). We aimed to identify the genetic variants associated with PNR., Patients and Methods: Patients were recruited from outpatient GI clinics and PNR was determined using both clinical and endoscopic findings. A case-control genome-wide association study was performed in 589 IBD patients and associations were replicated in an independent cohort of 293 patients. Effect of the associated variant on gene expression and TNFα secretion was assessed by cell-based assays. Pleiotropic effects were investigated by Phenome-wide association study (PheWAS)., Results: We identified rs34767465 as associated with PNR to anti-TNFα therapy (odds ratio: 2.07, 95% CI, 1.46-2.94, P = 2.43 × 10-7, [replication odds ratio: 1.8, 95% CI, 1.04-3.16, P = 0.03]). rs34767465 is a multiple-tissue expression quantitative trait loci for FAM114A2. Using RNA-sequencing and protein quantification from HapMap lymphoblastoid cell lines (LCLs), we found a significant decrease in FAM114A2 mRNA and protein expression in both heterozygous and homozygous genotypes when compared to wild type LCLs. TNFα secretion was significantly higher in THP-1 cells [differentiated into macrophages] with FAM114A2 knockdown versus controls. Immunoblotting experiments showed that depletion of FAM114A2 impaired autophagy-related pathway genes suggesting autophagy-mediated TNFα secretion as a potential mechanism. PheWAS showed rs34767465 was associated with comorbid conditions found in IBD patients (derangement of joints [P = 3.7 × 10-4], pigmentary iris degeneration [P = 5.9 × 10-4], diverticulum of esophagus [P = 7 × 10-4])., Conclusions: We identified a variant rs34767465 associated with PNR to anti-TNFα biologics, which increases TNFα secretion through mechanism related to autophagy. rs34767465 may also explain the comorbidities associated with IBD., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2022
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43. HIF-1α Pulmonary Phenotype Wide Association Study Unveils a Link to Inflammatory Airway Conditions.
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Kelchtermans J, Chang X, March ME, Mentch F, Sleiman PMA, and Hakonarson H
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Despite experimental data linking HIF-1α dysfunction to inflammatory airway conditions, the effect of single nucleotide polymorphisms within the HIF1A gene on these conditions remains poorly understood. In the current study, we complete a phenotype wide association study to assess the link between SNPs with known disease associations and respiratory phenotypes. We report two SNPs of the HIF1A gene, the intronic rs79865957 and the missense rs41508050. In these positions the A and the T allele are significantly associated with allergic rhinitis and acute bronchitis and bronchiolitis, respectively. These findings further support the role of HIF-1α in inflammatory pulmonary conditions and may serve as a basis to refine our understanding of other HIF-1α associated phenotypes., 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 © 2021 Kelchtermans, Chang, March, Mentch, Sleiman and Hakonarson.)
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- 2021
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44. Association Between a Common, Benign Genotype and Unnecessary Bone Marrow Biopsies Among African American Patients.
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Van Driest SL, Abul-Husn NS, Glessner JT, Bastarache L, Nirenberg S, Schildcrout JS, Eswarappa MS, Belbin GM, Shaffer CM, Mentch F, Connolly J, Shi M, Stein CM, Roden DM, Hakonarson H, Cox NJ, Borinstein SC, and Mosley JD
- Subjects
- Adult, Female, Gene Expression Profiling statistics & numerical data, Genetic Profile, Genome-Wide Association Study, Humans, Leukocyte Count, Male, Polymorphism, Single Nucleotide, United States epidemiology, Unnecessary Procedures methods, Unnecessary Procedures statistics & numerical data, Black or African American genetics, Biopsy methods, Biopsy statistics & numerical data, Bone Marrow Examination methods, Bone Marrow Examination statistics & numerical data, Duffy Blood-Group System genetics, Neutropenia diagnosis, Neutropenia ethnology, Neutropenia genetics, Receptors, Cell Surface genetics
- Abstract
Importance: Up to two-thirds of African American individuals carry the benign rs2814778-CC genotype that lowers total white blood cell (WBC) count., Objective: To examine whether the rs2814778-CC genotype is associated with an increased likelihood of receiving a bone marrow biopsy (BMB) for an isolated low WBC count., Design, Setting, and Participants: This retrospective genetic association study assessed African American patients younger than 90 years who underwent a BMB at Vanderbilt University Medical Center, Mount Sinai Health System, or Children's Hospital of Philadelphia from January 1, 1998, to December 31, 2020., Exposure: The rs2814778-CC genotype., Main Outcomes and Measures: The proportion of individuals with the CC genotype who underwent BMB for an isolated low WBC count and had a normal biopsy result compared with the proportion of individuals with the CC genotype who underwent BMB for other indications and had a normal biopsy result., Results: Among 399 individuals who underwent a BMB (mean [SD] age, 41.8 [22.5] years, 234 [59%] female), 277 (69%) had the CC genotype. A total of 35 patients (9%) had clinical histories of isolated low WBC counts, and 364 (91%) had other histories. Of those with a clinical history of isolated low WBC count, 34 of 35 (97%) had the CC genotype vs 243 of 364 (67%) of those without a low WBC count history. Among those with the CC genotype, 33 of 34 (97%) had normal results for biopsies performed for isolated low WBC counts compared with 134 of 243 individuals (55%) with biopsies performed for other histories (P < .001)., Conclusions and Relevance: In this genetic association study, among patients of African American race who had a BMB with a clinical history of isolated low WBC counts, the rs2814778-CC genotype was highly prevalent, and 97% of these BMBs identified no hematologic abnormality. Accounting for the rs2814778-CC genotype in clinical decision-making could avoid unnecessary BMB procedures.
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- 2021
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45. A Mendelian Randomization Approach Using 3-HMG-Coenzyme-A Reductase Gene Variation to Evaluate the Association of Statin-Induced Low-Density Lipoprotein Cholesterol Lowering With Noncardiovascular Disease Phenotypes.
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Liu G, Shi M, Mosley JD, Weng C, Zhang Y, Lee MTM, Jarvik GP, Hakonarson H, Namjou-Khales B, Sleiman P, Luo Y, Mentch F, Denny JC, Linton MF, Wei WQ, Stein CM, and Feng Q
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- Adult, Aged, Aged, 80 and over, Cohort Studies, Europe, Female, Humans, Male, Mendelian Randomization Analysis, Middle Aged, Odds Ratio, Cholesterol, LDL blood, Cholesterol, LDL genetics, Genetic Variation, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use, Hypercholesterolemia blood, Hypercholesterolemia drug therapy, Phenotype
- Abstract
Importance: Observational studies suggest that statins, which inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, may be associated with beneficial effects in many noncardiovascular diseases., Objective: To construct a weighted HMG-CoA reductase (HMGCR) gene genetic risk score (GRS) using variants in the HMGCR gene affecting low-density lipoprotein cholesterol as an instrumental variable for mendelian randomization analyses to test associations with candidate noncardiovascular phenotypes previously associated with statin use in observational studies., Design, Setting, and Participants: This cohort study included 53 385 unrelated adults of European ancestry with genome-wide genotypes available from BioVU (a practice-based biobank, used for discovery) and 30 444 unrelated adults with European ancestry available in the Electronic Medical Records and Genomics (eMERGE; a research consortium that conducts genetic research using electronic medical records, used for replication). The study was conducted from February 6, 2015, through April 31, 2019; data analysis was performed from August 26, 2019, through December 22, 2020., Interventions: An HMGCR GRS was calculated., Main Outcomes and Measures: The association between the HMGCR GRS and the presence or absence of 22 noncardiovascular phenotypes previously associated with statin use in clinical studies., Results: Of the 53 385 individuals in BioVU, 29 958 (56.1%) were women; mean (SD) age was 59.9 (15.6) years. The finding between the HMGCR GRS and the noncardiovascular phenotypes of interest in this cohort was significant only for type 2 diabetes. An HMGCR GRS equivalent to a 10-mg/dL decrease in the low-density lipoprotein cholesterol level was associated with an increased risk of type 2 diabetes (odds ratio [OR], 1.09; 95% CI, 1.04-1.15; P = 5.58 × 10-4). The HMGCR GRS was not associated with other phenotypes; the closest were increased risk of Parkinson disease (OR, 1.30; 95% CI, 1.07-1.58; P = .007) and kidney failure (OR, 1.18; 95% CI, 1.05-1.34; P = .008). Of the 30 444 individuals in eMERGE, 16 736 (55.0%) were women; mean (SD) age was 68.7 (15.4) years. The association between the HMGCR GRS and type 2 diabetes was replicated in this cohort (OR, 1.09; 95% CI, 1.01-1.17; P = .02); however, the HMGCR GRS was not associated with Parkinson disease (OR, 0.93; 95% CI, 0.75-1.16; P = .53) and kidney failure (OR, 1.18; 95% CI, 0.98-1.41; P = .08) in the eMERGE cohort., Conclusions and Relevance: A mendelian randomization approach using variants in the HMGCR gene replicated the association between statin use and increased type 2 diabetes risk but provided no strong evidence for pleiotropic effects of statin-induced decrease of the low-density lipoprotein cholesterol level on other diseases.
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- 2021
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46. A novel heterotaxy gene: Expansion of the phenotype of TTC21B-spectrum disease.
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Strong A, Li D, Mentch F, and Hakonarson H
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- Abnormalities, Multiple pathology, Cerebellum pathology, Child, Ciliary Motility Disorders complications, Ciliary Motility Disorders pathology, Eye Abnormalities complications, Eye Abnormalities pathology, Genetic Predisposition to Disease, Glomerulosclerosis, Focal Segmental complications, Glomerulosclerosis, Focal Segmental genetics, Glomerulosclerosis, Focal Segmental pathology, Heterotaxy Syndrome complications, Heterotaxy Syndrome pathology, Humans, Kidney metabolism, Kidney pathology, Kidney Diseases, Cystic complications, Kidney Diseases, Cystic genetics, Kidney Diseases, Cystic pathology, Kidney Transplantation, Male, Retina pathology, Exome Sequencing, Abnormalities, Multiple genetics, Cerebellum abnormalities, Ciliary Motility Disorders genetics, Eye Abnormalities genetics, Heterotaxy Syndrome genetics, Kidney Diseases, Cystic congenital, Microtubule-Associated Proteins genetics, Retina abnormalities
- Abstract
TTC21B encodes the protein IFT139, a critical component of the retrograde transport system within the primary cilium. Biallelic, pathogenic TTC21B variants are associated with classic ciliopathy syndromes, including nephronophthisis, Jeune asphyxiating thoracic dystrophy, and Joubert Syndrome, with ciliopathy-spectrum traits such as biliary dysgenesis, primary ciliary dyskinesia, and situs inversus, and also with focal segmental glomerulosclerosis. We report a 9-year-old male with focal segmental glomerulosclerosis requiring kidney transplant, primary ciliary dyskinesia, and biliary dysgenesis, found by research-based exome sequencing to have biallelic pathogenic TTC21B variants. A sibling with isolated heterotaxy was found to harbor the same variants. This case highlights the phenotypic spectrum and unpredictable manifestations of TTC21B-related disease, and also reports the first association between TTC21B and heterotaxy, nominating TTC21B as an important new heterotaxy gene., (© 2021 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)
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- 2021
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47. Response to Li and Hopper.
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Thomas M, Sakoda LC, Hoffmeister M, Rosenthal EA, Lee JK, van Duijnhoven FJB, Platz EA, Wu AH, Dampier CH, de la Chapelle A, Wolk A, Joshi AD, Burnett-Hartman A, Gsur A, Lindblom A, Castells A, Win AK, Namjou B, Van Guelpen B, Tangen CM, He Q, Li CI, Schafmayer C, Joshu CE, Ulrich CM, Bishop DT, Buchanan DD, Schaid D, Drew DA, Muller DC, Duggan D, Crosslin DR, Albanes D, Giovannucci EL, Larson E, Qu F, Mentch F, Giles GG, Hakonarson H, Hampel H, Stanaway IB, Figueiredo JC, Huyghe JR, Minnier J, Chang-Claude J, Hampe J, Harley JB, Visvanathan K, Curtis KR, Offit K, Li L, Le Marchand L, Vodickova L, Gunter MJ, Jenkins MA, Slattery ML, Lemire M, Woods MO, Song M, Murphy N, Lindor NM, Dikilitas O, Pharoah PDP, Campbell PT, Newcomb PA, Milne RL, MacInnis RJ, Castellví-Bel S, Ogino S, Berndt SI, Bézieau S, Thibodeau SN, Gallinger SJ, Zaidi SH, Harrison TA, Keku TO, Hudson TJ, Vymetalkova V, Moreno V, Martín V, Arndt V, Wei WQ, Chung W, Su YR, Hayes RB, White E, Vodicka P, Casey G, Gruber SB, Schoen RE, Chan AT, Potter JD, Brenner H, Jarvik GP, Corley DA, Peters U, and Hsu L
- Subjects
- Humans, Risk Factors, Colorectal Neoplasms
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- 2021
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48. Ciliopathies: Coloring outside of the lines.
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Strong A, Li D, Mentch F, Bedoukian E, Hartung EA, Meyers K, Skraban C, Wen J, Medne L, Glessner J, Watson D, Krantz I, and Hakonarson H
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- Abnormalities, Multiple genetics, Adult, Child, Child, Preschool, Ciliopathies genetics, Female, High-Throughput Nucleotide Sequencing, Humans, Male, Phenotype, Prognosis, Abnormalities, Multiple pathology, Chaperonins genetics, Ciliopathies pathology, Cytoplasmic Dyneins genetics, Cytoskeletal Proteins genetics, Intracellular Signaling Peptides and Proteins genetics, Microtubule-Associated Proteins genetics, Mutation
- Abstract
Ciliopathy syndromes are a diverse spectrum of disease characterized by a combination of cystic kidney disease, hepatobiliary disease, retinopathy, skeletal dysplasia, developmental delay, and brain malformations. Though generally divided into distinct disease categories based on the pattern of system involvement, ciliopathy syndromes are known to display certain phenotypic overlap. We performed next-generation sequencing panel testing, clinical exome sequencing, and research-based exome sequencing reanalysis on patients with suspected ciliopathy syndromes with additional features. We identified biallelic pathogenic variants in BBS1 in a child with features of cranioectodermal dysplasia, and biallelic variants in BBS12 in a child with the clinical stigmata of Bardet-Biedl syndrome, but also with anal atresia. We additionally identified biallelic pathogenic variants in WDR35 and DYNC2H1 in children with predominant liver disease and ductal plate malformation without skeletal dysplasia. Our study highlights the phenotypic and genetic diversity of ciliopathy syndromes, the importance of considering ciliopathy syndromes as a disease-spectrum and screening for all associated complications in all patients, and describes exclusive extra-skeletal manifestations in two classical skeletal dysplasia syndromes., (© 2020 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)
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- 2021
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49. Unsupervised modeling and genome-wide association identify novel features of allergic march trajectories.
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Gabryszewski SJ, Chang X, Dudley JW, Mentch F, March M, Holmes JH, Moore J, Grundmeier RW, Hakonarson H, and Hill DA
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- Adolescent, Child, Child, Preschool, Cluster Analysis, Decision Trees, Female, Genome-Wide Association Study, Humans, Infant, Male, Racial Groups, Disease Progression, Hypersensitivity ethnology, Hypersensitivity genetics
- Abstract
Background: The allergic march refers to the natural history of allergic conditions during infancy and childhood. However, population-level disease incidence patterns do not necessarily reflect the development of allergic disease in individuals. A better understanding of the factors that predispose to different allergic trajectories is needed., Objective: Our aim was to determine the demographic and genetic features that are associated with the major allergic march trajectories., Methods: Presence or absence of common allergic conditions (atopic dermatitis [AD], IgE-mediated food allergy [IgE-FA], asthma, and allergic rhinitis [AR]) was ascertained in a pediatric primary care birth cohort of 158,510 subjects. Hierarchic clustering and decision tree modeling were used to associate demographic features with allergic outcomes. Genome-wide association study was used to test for risk loci associated with specific allergic trajectories., Results: We found an association between self-identified black race and progression from AD to asthma. Conversely, Asian or Pacific Islander race was associated with progression from AD to IgE-mediated food allergy, and white race was associated with progression from AD to AR. Genome-wide association study of trajectory groups identified risk loci associated with progression from AD to asthma (rs60242841) and from AD to AR (rs9565267, rs151041509, and rs78171803). Consistent with our epidemiologic associations, rs60242841 was more common in individuals of African ancestry than in individuals of European ancestry, whereas rs9565267 and rs151041509 were more common in individuals of European ancestry than in individuals of African ancestry., Conclusion: We have identified novel associations between race and progression along distinct allergic trajectories. Ancestral genetic differences may contribute to these associations. These results uncover important health disparities, refine the concept of the allergic march, and represent a step toward developing individualized medical approaches for these conditions., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)
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- 2021
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50. Mitochondrial DNA haplogroups and risk of attention deficit and hyperactivity disorder in European Americans.
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Chang X, Liu Y, Mentch F, Glessner J, Qu H, Nguyen K, Sleiman PMA, and Hakonarson H
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- Case-Control Studies, Child, DNA, Mitochondrial genetics, Haplotypes, Humans, Mitochondria genetics, Attention Deficit Disorder with Hyperactivity genetics
- Abstract
Although mitochondrial dysfunction has been implicated in the pathophysiology of attention deficit and hyperactivity disorder ADHD, the role of mitochondrial DNA (mtDNA) has not been extensively investigated. To determine whether mtDNA haplogroups influence risk of ADHD, we performed a case-control study comprising 2076 ADHD cases and 5078 healthy controls, all of whom were European decedents recruited from The Children's Hospital of Philadelphia (CHOP). Associations between eight major European mtDNA Haplogroups and ADHD risk were assessed in three independent European cohorts. Meta-analysis of the three studies indicated that mtDNA haplogroups K (odds ratio = 0.69, P = 2.24 × 10
-4 , Pcorrected = 1.79 × 10-3 ) and U (odds ratio = 0.77, P = 8.88 × 10-4 , Pcorrected = 7.11 × 10-3 ) were significantly associated with reduced risk of ADHD. In contrast, haplogroup HHV* (odds ratio = 1.18, P = 2.32 × 10-3 , Pcorrected = 0.019) was significantly associated with increased risk of ADHD. Our results provide novel insight into the genetic basis of ADHD, implicating mitochondrial mechanisms in the pathophysiology of this relatively common psychiatric disorder.- Published
- 2020
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