The Huang lab is a member of the Stanley Center Global and leads the Stanley Center Asia Initiatives. Therefore, we are particularly interested in psychiatric genetics research problems in the Asia populations and across global populations. Working with the Psychiatric Genomics Consortium, the Huang lab led a study to compile over 22,000 schizophrenia cases and 35,000 controls of East Asia ancestry (Lam and Chen et al, Nature Genetics 2019). Using this largest to date psychiatric genetics cohort of East Asia ancestry, we identified 176 genetic loci (53 new) associated with schizophrenia. We also found that genetic variants that confer risk to schizophrenia have highly similar effects in those of East Asian and European ancestry, indicating for the first time that the genetic basis of schizophrenia and its biology are broadly shared across these world populations. A novel fine-mapping method enabled by the diversity in linkage disequilibrium across ancestries more precisely isolated schizophrenia causal alleles in 70% of genetic regions. We also found genetic risk prediction has reduced performance when used across populations, highlighting the importance of including all major ancestral groups with sufficient sample size to ensure the findings have maximum relevance for all populations.
Other psychiatric genetics studies in the Huang lab include understanding contributions from structural variations and copy number variations to schizophrenia in East Asia populations and studies to identify neurophysiology biomarkers for schizophrenia.
Selected Publications
Comparative genetic architectures of schizophrenia in East Asian and European populations
Lam M, Chen CY, Li Z, Martin A, Bryois J, Ma X, Gaspar H, Ikeda M, Benyamin B, Brown B, Liu R, Zhou W, Guan L, Kamatani Y, Kim SW, Kubo M, Kusumawardhani A, Liu CM, Ma H, Periyasamy S, Takahashi A, Wang Q, Xu Z, Yu H, Zhu F, Psychiatric Genomics Consortium Schizophrenia Working Group, Indonesia Schizophrenia Consortium, Genetic REsearch on schizophreniA neTwork-China, Netherland GREAT-CN, Chen W, Faraone S, Glatt S, He L, Hyman S, Hwu HG, Li T, McCarroll S, Neale B, Sklar P, Wildenauer D, Yu X, Zhang D, Mowry B, Lee J, Holmans P, Xu S, Sullivan P, Ripke S, O'Donovan M, Daly M, Qin S, Sham P, Iwata N, Hong K, Schwab S, Yue W, Tsuang M, Liu J, Ma X, Kahn R, Shi Y, and Huang H. Comparative genetic architectures of schizophrenia in East Asian and European populations., Nature genetics, 51(12), 1670–1678. [DOI] [PubMed]Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder
Demontis D, Walters RK, Martin J, Mattheisen M, Als TD, Agerbo E, Baldursson G, Belliveau R, Bybjerg-Grauholm J, Bækvad-Hansen M, Cerrato F, Chambert K, Churchhouse C, Dumont A, Eriksson N, Gandal M, Goldstein JI, Grasby KL, Grove J, Gudmundsson OO, Hansen CS, Hauberg ME, Hollegaard MV, Howrigan DP, Huang H, Maller JB, Martin AR, Martin NG, Moran J, Pallesen J, Palmer DS, Pedersen CB, Pedersen MG, Poterba T, Poulsen JB, Ripke S, Robinson EB, Satterstrom FK, Stefansson H, Stevens C, Turley P, Walters GB, Won H, Wright MJ, Andreassen OA, Asherson P, Burton CL, Boomsma DI, Cormand B, Dalsgaard S, Franke B, Gelernter J, Geschwind D, Hakonarson H, Haavik J, Kranzler HR, Kuntsi J, Langley K, Lesch KP, Middeldorp C, Reif A, Rohde LA, Roussos P, Schachar R, Sklar P, Sonuga-Barke EJS, Sullivan PF, Thapar A, Tung JY, Waldman ID, Medland SE, Stefansson K, Nordentoft M, Hougaard DM, Werge T, Mors O, Mortensen PB, Daly MJ, Faraone SV, Børglum AD, Neale BM. Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder. Nat Genet. 2019 Jan;51(1):63-75. Epub 2018 Nov 26 [DOI] [PubMed] [PubMed Central]Genome-wide Association Studies in Ancestrally Diverse Populations: Opportunities, Methods, Pitfalls, and Recommendation
Peterson RE, Kuchenbaecker K, Walters RK, Chen CY, Popejoy AB, Periyasamy S, Lam M, Iyegbe C, Strawbridge RJ, Brick L, Carey CE, Martin AR, Meyers JL, Su J, Chen J, Edwards AC, Kalungi A, Koen N, Majara L, Schwarz E, Smoller JW, Stahl EA, Sullivan PF, Vassos E, Mowry B, Prieto ML, Cuellar-Barboza A, Bigdeli TB, Edenberg HJ, Huang H, Duncan LE. Genome-wide Association Studies in Ancestrally Diverse Populations: Opportunities, Methods, Pitfalls, and Recommendations. Cell. 2019 Oct 17;179(3):589-603. Epub 2019 Oct 10. [DOI] [PubMed]Identification of common genetic risk variants for autism spectrum disorder
Grove J, Ripke S, Als TD, Mattheisen M, Walters RK, Won H, Pallesen J, Agerbo E, Andreassen OA, Anney R, Awashti S, Belliveau R, Bettella F, Buxbaum JD, Bybjerg-Grauholm J, Bækvad-Hansen M, Cerrato F, Chambert K, Christensen JH, Churchhouse C, Dellenvall K, Demontis D, De Rubeis S, Devlin B, Djurovic S, Dumont AL, Goldstein JI, Hansen CS, Hauberg ME, Hollegaard MV, Hope S, Howrigan DP, Huang H, Hultman CM, Klei L, Maller J, Martin J, Martin AR, Moran JL, Nyegaard M, Nærland T, Palmer DS, Palotie A, Pedersen CB, Pedersen MG, dPoterba T, Poulsen JB, Pourcain BS, Qvist P, Rehnström K, Reichenberg A, Reichert J, Robinson EB, Roeder K, Roussos P, Saemundsen E, Sandin S, Satterstrom FK, Davey Smith G, Stefansson H, Steinberg S, Stevens CR, Sullivan PF, Turley P, Walters GB, Xu X, Stefansson K, Geschwind DH, Nordentoft M, Hougaard DM, Werge T, Mors O, Mortensen PB, Neale BM, Daly MJ, Børglum AD. Identification of common genetic risk variants for autism spectrum disorder. Nat Genet. 2019 Mar;51(3):431-444. Epub 2019 Feb 25 [DOI] [PubMed] [PubMed Central]Blood transcriptomic comparison of individuals with and without autism spectrum disorder: A combined-samples mega-analysis
Peterson RE, Kuchenbaecker K, Walters RK, Chen CY, Popejoy AB, Periyasamy S, Lam M, Iyegbe C, Strawbridge RJ, Brick L, Carey CE, Martin AR, Meyers JL, Su J, Chen J, Edwards AC, Kalungi A, Koen N, Majara L, Schwarz E, Smoller JW, Stahl EA, Sullivan PF, Vassos E, Mowry B, Prieto ML, Cuellar-Barboza A, Bigdeli TB, Edenberg HJ, Huang H, Duncan LE. Genome-wide Association Studies in Ancestrally Diverse Populations: Opportunities, Methods, Pitfalls, and Recommendations. Cell. 2019 Oct 17;179(3):589-603. Epub 2019 Oct 10. [DOI] [PubMed]Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects
Lam M, Chen CY, Li Z, Martin A, Bryois J, Ma X, Gaspar H, Ikeda M, Benyamin B, Brown B, Liu R, Zhou W, Guan L, Kamatani Y, Kim SW, Kubo M, Kusumawardhani A, Liu CM, Ma H, Periyasamy S, Takahashi A, Xu Z, Yu H, Zhu F, Psychiatric Genomics Consortium Schizophrenia Working Group, Indonesia Schizophrenia Consortium, Genetic REsearch on schizophreniA neTwork-China, Netherland GREAT-CN, Chen W, Faraone S, Glatt S, He L, Hyman S, Hwu HG, Li T, McCarroll S, Neale B, Sklar P, Wildenauer D, Yu X, Zhang D, Mowry B, Lee J, Holmans P, Xu S, Sullivan P, Ripke S, O'Donovan M, Daly M, Qin S, Sham P, Iwata N, Hong K, Schwab S, Yue W, Tsuang M, Liu J, Ma X, Kahn R, Shi Y, and Huang H. Comparative genetic architectures of schizophrenia in East Asian and European populations., Nature Genetics (accepted on June 5 2019)Whole genome sequencing in psychiatric disorders: the WGSPD consortium
Sanders SJ, Neale BM, Huang H, Werling DM, An JY, Dong S, Abecasis G, Arguello PA, Blangero J, Boehnke M, Daly MJ, Eggan K, Geschwind DH, Glahn DC, Goldstein DB, Gur RE, Handsaker RE, McCarroll SA, Ophoff RA, Palotie A, Pato CN, Sabatti C, State MW, Willsey AJ, Hyman SE, Addington AM, Lehner T, Freimer NB. Whole genome sequencing in psychiatric disorders: the WGSPD consortium. Nat Neurosci. 2017 Dec;20(12):1661-1668. Review [DOI] [PubMed]Clozapine-induced agranulocytosis is associated with rare HLA-DQB1 and HLA-B alleles
Jacqueline I Goldstein, Fredrik L Jarskog, Chris Hilliard, Ana Alfirevic, Laramie Duncan, Denis Fourches, Hailiang Huang, Monkol Lek, Benjamin M Neale, Stephan Ripke, Kevin Shianna, Jin P Szatkiewicz, Alexander Tropsha, Edwin JCG van den Oord, Ingolf Cascorbi, Michael Dettling, Ephraim Gazit, Donald C Goff, Arthur L Holden, Deanna L Kelly, Anil K Malhotra, Jimmi Nielsen, Munir Pirmohamed, Dan Rujescu, Thomas Werge, Deborah L Levy, Richard C Josiassen, James L Kennedy, Jeffrey A Lieberman, Mark J Daly, and Patrick F Sullivan. 2014. “Clozapine-induced agranulocytosis is associated with rare HLA-DQB1 and HLA-B alleles.” Nat Commun, 5, Pp. 4757. AbstractClozapine is a particularly effective antipsychotic medication but its use is curtailed by the risk of clozapine-induced agranulocytosis/granulocytopenia (CIAG), a severe adverse drug reaction occurring in up to 1% of treated individuals. Identifying genetic risk factors for CIAG could enable safer and more widespread use of clozapine. Here we perform the largest and most comprehensive genetic study of CIAG to date by interrogating 163 cases using genome-wide genotyping and whole-exome sequencing. We find that two loci in the major histocompatibility complex are independently associated with CIAG: a single amino acid in HLA-DQB1 (126Q) (P=4.7 × 10(-14), odds ratio (OR)=0.19, 95% confidence interval (CI)=0.12-0.29) and an amino acid change in the extracellular binding pocket of HLA-B (158T) (P=6.4 × 10(-10), OR=3.3, 95% CI=2.3-4.9). These associations dovetail with the roles of these genes in immunogenetic phenotypes and adverse drug responses for other medications, and provide insight into the pathophysiology of CIAG.
