Association of Parkinson disease with structural and regulatory variants in the HLA region - PubMed (original) (raw)

Association of Parkinson disease with structural and regulatory variants in the HLA region

William T Wissemann et al. Am J Hum Genet. 2013.

Abstract

Historically, association of disease with the major histocompatibility complex (HLA) genes has been tested with HLA alleles that encode antigen-binding affinity. The association with Parkinson disease (PD), however, was discovered with noncoding SNPs in a genome-wide association study (GWAS). We show here that several HLA-region SNPs that have since been associated with PD form two blocks tagged by rs3129882 (p = 9 × 10(-11)) and by rs9268515 and/or rs2395163 (p = 3 × 10(-11)). We investigated whether these SNP-associations were driven by HLA-alleles at adjacent loci. We imputed class I and class II HLA-alleles for 2000 PD cases and 1986 controls from the NeuroGenetics Research Consortium GWAS and sequenced a subset of 194 cases and 204 controls. We were therefore able to assess accuracy of two imputation algorithms against next-generation-sequencing while taking advantage of the larger imputed data sets for disease study. Additionally, we imputed HLA alleles for 843 cases and 856 controls from another GWAS for replication. PD risk was positively associated with the B(∗)07:02_C(∗)07:02_DRB5(∗)01_DRB1(∗)15:01_DQA1(∗)01:02_DQB1(∗)06:02 haplotype and negatively associated with the C(∗)03:04, DRB1(∗)04:04 and DQA1(∗)03:01 alleles. The risk haplotype and DQA1(∗)03:01 lost significance when conditioned on the SNPs, but C(∗)03:04 (OR = 0.72, p = 8 × 10(-6)) and DRB1(∗)04:04 (OR = 0.65, p = 4 × 10(-5)) remained significant. Similarly, rs3129882 and the closely linked rs9268515 and rs2395163 remained significant irrespective of HLA alleles. rs3129882 and rs2395163 are expression quantitative trait loci (eQTLs) for HLA-DR and HLA-DQ (9 × 10(-5) ≥ PeQTL ≥ 2 × 10(-79)), suggesting that HLA gene expression might influence PD. Our data suggest that PD is associated with both structural and regulatory elements in HLA. Furthermore, our study demonstrates that noncoding SNPs in the HLA region can be associated with disease irrespective of HLA alleles, and that observed associations with HLA alleles can sometimes be secondary to a noncoding variant.

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Figures

Figure 1

HLA and PD-Associated Variants (A) Map of HLA class I and class II genes. (B) PD-associated SNPs from our studies and the literature. (C) Linkage disequilibrium, measured by correlation coefficient (r2 values shown in boxes), among five PD-associated SNPs and 12 PD-associated HLA alleles identified in the present study. rs41269955 is the proxy used for rs75855844 in NGRC.

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References

1. Hamza T.H., Zabetian C.P., Tenesa A., Laederach A., Montimurro J., Yearout D., Kay D.M., Doheny K.F., Paschall J., Pugh E. Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson’s disease. Nat. Genet. 2010;42:781–785. - PMC - PubMed
1. Nalls M.A., Plagnol V., Hernandez D.G., Sharma M., Sheerin U.M., Saad M., Simón-Sánchez J., Schulte C., Lesage S., Sveinbjörnsdóttir S., International Parkinson Disease Genomics Consortium Imputation of sequence variants for identification of genetic risks for Parkinson’s disease: a meta-analysis of genome-wide association studies. Lancet. 2011;377:641–649. - PMC - PubMed
1. Hill-Burns E.M., Factor S.A., Zabetian C.P., Thomson G., Payami H. Evidence for more than one Parkinson’s disease-associated variant within the HLA region. PLoS ONE. 2011;6:e27109. - PMC - PubMed
1. Pankratz N., Beecham G.W., DeStefano A.L., Dawson T.M., Doheny K.F., Factor S.A., Hamza T.H., Hung A.Y., Hyman B.T., Ivinson A.J., PD GWAS Consortium Meta-analysis of Parkinson’s disease: identification of a novel locus, RIT2. Ann. Neurol. 2012;71:370–384. - PMC - PubMed
1. Ahmed I., Tamouza R., Delord M., Krishnamoorthy R., Tzourio C., Mulot C., Nacfer M., Lambert J.C., Beaune P., Laurent-Puig P. Association between Parkinson’s disease and the HLA-DRB1 locus. Mov. Disord. 2012;27:1104–1110. - PubMed

Association of Parkinson disease with structural and regulatory variants in the HLA region - PubMed (original) (raw)