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Classical Human Leukocyte Antigen Alleles and C4 Haplotypes Are Not Significantly Associated With Depression.

ABSTRACT: BACKGROUND:The prevalence of depression is higher in individuals with autoimmune diseases, but the mechanisms underlying the observed comorbidities are unknown. Shared genetic etiology is a plausible explanation for the overlap, and in this study we tested whether genetic variation in the major histocompatibility complex (MHC), which is associated with risk for autoimmune diseases, is also associated with risk for depression. METHODS:We fine-mapped the classical MHC (chr6: 29.6-33.1 Mb), imputing 216 human leukocyte antigen (HLA) alleles and 4 complement component 4 (C4) haplotypes in studies from the Psychiatric Genomics Consortium Major Depressive Disorder Working Group and the UK Biobank. The total sample size was 45,149 depression cases and 86,698 controls. We tested for association between depression status and imputed MHC variants, applying both a region-wide significance threshold (3.9 × 10-6) and a candidate threshold (1.6 × 10-4). RESULTS:No HLA alleles or C4 haplotypes were associated with depression at the region-wide threshold. HLA-B*08:01 was associated with modest protection for depression at the candidate threshold for testing in HLA genes in the meta-analysis (odds ratio = 0.98, 95% confidence interval = 0.97-0.99). CONCLUSIONS:We found no evidence that an increased risk for depression was conferred by HLA alleles, which play a major role in the genetic susceptibility to autoimmune diseases, or C4 haplotypes, which are strongly associated with schizophrenia. These results suggest that any HLA or C4 variants associated with depression either are rare or have very modest effect sizes.

SUBMITTER: Glanville KP

PROVIDER: S-EPMC7001040 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Classical Human Leukocyte Antigen Alleles and C4 Haplotypes Are Not Significantly Associated With Depression.

Glanville Kylie P KP Coleman Jonathan R I JRI Hanscombe Ken B KB Euesden Jack J Choi Shing Wan SW Purves Kirstin L KL Breen Gerome G Air Tracy M TM Andlauer Till F M TFM Baune Bernhard T BT Binder Elisabeth B EB Blackwood Douglas H R DHR Boomsma Dorret I DI Buttenschøn Henriette N HN Colodro-Conde Lucía L Dannlowski Udo U Direk Nese N Dunn Erin C EC Forstner Andreas J AJ de Geus Eco J C EJC Grabe Hans J HJ Hamilton Steven P SP Jones Ian I Jones Lisa A LA Knowles James A JA Kutalik Zoltán Z Levinson Douglas F DF Lewis Glyn G Lind Penelope A PA Lucae Susanne S Magnusson Patrik K PK McGuffin Peter P McIntosh Andrew M AM Milaneschi Yuri Y Mors Ole O Mostafavi Sara S Müller-Myhsok Bertram B Pedersen Nancy L NL Penninx Brenda W J H BWJH Potash James B JB Preisig Martin M Ripke Stephan S Shi Jianxin J Shyn Stanley I SI Smoller Jordan W JW Streit Fabian F Sullivan Patrick F PF Tiemeier Henning H Uher Rudolf R Van der Auwera Sandra S Weissman Myrna M MM O'Reilly Paul F PF Lewis Cathryn M CM

Biological psychiatry 20190805 5

<h4>Background</h4>The prevalence of depression is higher in individuals with autoimmune diseases, but the mechanisms underlying the observed comorbidities are unknown. Shared genetic etiology is a plausible explanation for the overlap, and in this study we tested whether genetic variation in the major histocompatibility complex (MHC), which is associated with risk for autoimmune diseases, is also associated with risk for depression.<h4>Methods</h4>We fine-mapped the classical MHC (chr6: 29.6-33 ...[more]

PMID: 31570195

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Project description:BackgroundAssociations between human leukocyte antigens (HLA) alleles and cervical cancer are largely representative of squamous cell carcinoma (SCC), the major histologic subtype. We evaluated the association between HLA class I (A, B, and C) and class II (DRB1 and DQB1) loci and risk of cervical adenocarcinoma (ADC), a less common but aggressive histologic subtype.MethodsWe pooled data from the Eastern and Western US Cervical Cancer studies, and evaluated the association between individual alleles and allele combinations and ADC (n = 630 ADC; n = 775 controls). Risk estimates were calculated for 11 a priori (based on known associations with cervical cancer regardless of histologic type) and 38 non a priori common alleles, as odds ratios (OR) and 95% confidence intervals (CI), adjusted for age and study. In exploratory analysis, we compared the risk associations between subgroups with HPV16 or HPV18 DNA in ADC tumor tissues in the Western US study cases and controls.ResultsThree of the a priori alleles were significantly associated with decreased risk of ADC [DRB1*13:01 (OR = 0.61; 95% CI: 0.41-0.93), DRB1*13:02 (OR = 0.49; 95% CI: 0.31-0.77), and DQB1*06:03 (OR = 0.64; 95% CI: 0.42-0.95)]; one was associated with increased risk [B*07:02 (OR = 1.39; 95% CI: 1.07-1.79)]. Among alleles not previously reported, DQB1*06:04 (OR = 0.46; 95% CI: 0.27-0.78) was associated with decreased risk of ADC and remained significant after correction for multiple comparisons, and C*07:02 (OR = 1.41; 95% CI: 1.09-1.81) was associated with increased risk. We did not observe a difference by histologic subtype. ADC was most strongly associated with increased risk with B*07:02/C*07:02 alleles (OR = 1.33; 95% CI: 1.01-1.76) and decreased risk with DRB1*13:02/DQB1*06:04 (OR = 0.41; 95% CI: 0.21-0.80).ConclusionRESULTS suggest that HLA allele associations with cervical ADC are similar to those for cervical SCC. An intriguing finding was the difference in risk associated with several alleles restricted to HPV16 or HPV18-related tumors, consistent with the hypothesis that HLA recognition is HPV type-specific.

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Classical Human Leukocyte Antigen Alleles and C4 Haplotypes Are Not Significantly Associated With Depression.

Publications

Classical Human Leukocyte Antigen Alleles and C4 Haplotypes Are Not Significantly Associated With Depression.

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