Additive genetic variation in schizophrenia risk is shared by populations of African and European descent

de Candia, Teresa R., Lee, S. Hong, Yang, Jian, Browning, Brian L., Gejman, Pablo V., Levinson, Douglas F., Mowry, Bryan J., Hewitt, Bryan J., Goddard, Michael E., O'Donovan, Michael C., Purcell, Shaun M., Posthuma, Danielle, The International Schizophrenia Consortium, The Molecular Genetics of Schizophrenia Collaboration, Visscher, Peter M., Wray, Naomi R. and Keller, Matthew C. (2013) Additive genetic variation in schizophrenia risk is shared by populations of African and European descent. American Journal of Human Genetics, 93 3: 463-470. doi:10.1016/j.ajhg.2013.07.007

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Author de Candia, Teresa R.
Lee, S. Hong
Yang, Jian
Browning, Brian L.
Gejman, Pablo V.
Levinson, Douglas F.
Mowry, Bryan J.
Hewitt, Bryan J.
Goddard, Michael E.
O'Donovan, Michael C.
Purcell, Shaun M.
Posthuma, Danielle
The International Schizophrenia Consortium
The Molecular Genetics of Schizophrenia Collaboration
Visscher, Peter M.
Wray, Naomi R.
Keller, Matthew C.
Title Additive genetic variation in schizophrenia risk is shared by populations of African and European descent
Journal name American Journal of Human Genetics   Check publisher's open access policy
ISSN 0002-9297
1537-6605
Publication date 2013-09-05
Year available 2013
Sub-type Article (original research)
DOI 10.1016/j.ajhg.2013.07.007
Open Access Status File (Author Post-print)
Volume 93
Issue 3
Start page 463
End page 470
Total pages 8
Place of publication Cambridge, MA, United States
Publisher Cell Press
Language eng
Abstract Previous studies have emphasized ethnically heterogeneous human leukocyte antigen (HLA) classical allele associations to rheumatoid arthritis (RA) risk. We fine-mapped RA risk alleles within the major histocompatibility complex (MHC) in 2782 seropositive RA cases and 4315 controls of Asian descent. We applied imputation to determine genotypes for eight class I and II HLA genes to Asian populations for the first time using a newly constructed pan-Asian reference panel. First, we empirically measured high imputation accuracy in Asian samples. Then we observed the most significant association in HLA-DRβ1 at amino acid position 13, located outside the classical shared epitope (Pomnibus = 6.9 × 10(-135)). The individual residues at position 13 have relative effects that are consistent with published effects in European populations (His > Phe > Arg > Tyr ≅ Gly > Ser)--but the observed effects in Asians are generally smaller. Applying stepwise conditional analysis, we identified additional independent associations at positions 57 (conditional Pomnibus = 2.2 × 10(-33)) and 74 (conditional Pomnibus = 1.1 × 10(-8)). Outside of HLA-DRβ1, we observed independent effects for amino acid polymorphisms within HLA-B (Asp9, conditional P = 3.8 × 10(-6)) and HLA-DPβ1 (Phe9, conditional P = 3.0 × 10(-5)) concordant with European populations. Our trans-ethnic HLA fine-mapping study reveals that (i) a common set of amino acid residues confer shared effects in European and Asian populations and (ii) these same effects can explain ethnically heterogeneous classical allelic associations (e.g. HLA-DRB1*09:01) due to allele frequency differences between populations. Our study illustrates the value of high-resolution imputation for fine-mapping causal variants in the MHC.
Formatted abstract
To investigate the extent to which the proportion of schizophrenia’s additive genetic variation tagged by SNPs is shared by populations of European and African descent, we analyzed the largest combined African descent (AD [n = 2,142]) and European descent (ED [n = 4,990]) schizophrenia case-control genome-wide association study (GWAS) data set available, the Molecular Genetics of Schizophrenia (MGS) data set. We show how a method that uses genomic similarities at measured SNPs to estimate the additive genetic correlation (SNP correlation [SNP-rg]) between traits can be extended to estimate SNP-rg for the same trait between ethnicities. We estimated SNP-rg for schizophrenia between the MGS ED and MGS AD samples to be 0.66 (SE = 0.23), which is significantly different from 0 (p(SNP-rg = 0) = 0.0003), but not 1 (p(SNP-rg = 1) = 0.26). We re-estimated SNP-rg between an independent ED data set (n = 6,665) and the MGS AD sample to be 0.61 (SE = 0.21, p(SNP-rg = 0) = 0.0003, p(SNP-rg = 1) = 0.16). These results suggest that many schizophrenia risk alleles are shared across ethnic groups and predate African-European divergence.
Keyword Genetics & Heredity
Genetics & Heredity
GENETICS & HEREDITY
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID 1R01AR062886-01
1R01AR063759-01A1
5U01GM092691-04
R01 AR063759
MANMKBRU-2012-1
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Queensland Brain Institute Publications
Official 2014 Collection
 
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Citation counts: TR Web of Science Citation Count  Cited 29 times in Thomson Reuters Web of Science Article | Citations
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Created: Thu, 03 Oct 2013, 19:22:18 EST by Debra McMurtrie on behalf of Queensland Brain Institute