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.
| Original language | English |
|---|---|
| Pages (from-to) | 1-12 |
| Number of pages | 12 |
| Journal | Biological Psychiatry |
| DOIs | |
| Publication status | E-pub ahead of print - 5 Aug 2019 |
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Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.Cite this
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Classical Human Leukocyte Antigen Alleles and C4 Haplotypes Are Not Significantly Associated With Depression. / Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium; Abdellaoui, A.; Dolan, C.V.; Hottenga, Jouke Jan ; Jansen, Rick; Mbarek, Hamdi; Middeldorp, C.M.; Milaneschi, Yusplitri; Nivard, Michel; Peyrot, Wouter J; Posthuma, Danielle; Willemsen, Gonneke.
In: Biological Psychiatry, 05.08.2019, p. 1-12.Research output: Contribution to Journal › Article › Academic › peer-review
TY - JOUR
T1 - Classical Human Leukocyte Antigen Alleles and C4 Haplotypes Are Not Significantly Associated With Depression
AU - Glanville, Kylie P
AU - Coleman, Jonathan R I
AU - Hanscombe, Ken B
AU - Euesden, Jack
AU - Choi, Shing Wan
AU - Purves, Kirstin L
AU - Breen, Gerome
AU - Air, Tracy M
AU - Andlauer, Till F M
AU - Baune, Bernhard T
AU - Binder, Elisabeth B
AU - Blackwood, Douglas H R
AU - Boomsma, Dorret I
AU - Buttenschøn, Henriette N
AU - Colodro-Conde, Lucía
AU - Dannlowski, Udo
AU - Direk, Nese
AU - Dunn, Erin C
AU - Forstner, Andreas J
AU - de Geus, Eco J C
AU - Grabe, Hans J
AU - Hamilton, Steven P
AU - Jones, Ian
AU - Jones, Lisa A
AU - Knowles, James A
AU - Kutalik, Zoltán
AU - Levinson, Douglas F
AU - Lewis, Glyn
AU - Lind, Penelope A
AU - Lucae, Susanne
AU - Magnusson, Patrik K
AU - McGuffin, Peter
AU - McIntosh, Andrew M
AU - Milaneschi, Yuri
AU - Mors, Ole
AU - Mostafavi, Sara
AU - Müller-Myhsok, Bertram
AU - Pedersen, Nancy L
AU - Penninx, Brenda W J H
AU - Potash, James B
AU - Preisig, Martin
AU - Ripke, Stephan
AU - Shi, Jianxin
AU - Shyn, Stanley I
AU - Smoller, Jordan W
AU - Streit, Fabian
AU - Sullivan, Patrick F
AU - Tiemeier, Henning
AU - Uher, Rudolf
AU - Van der Auwera, Sandra
AU - Weissman, Myrna M
AU - O'Reilly, Paul F
AU - Lewis, Cathryn M
AU - Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium
AU - Abdellaoui, A.
AU - Dolan, C.V.
AU - Hottenga, Jouke Jan
AU - Jansen, Rick
AU - Mbarek, Hamdi
AU - Middeldorp, C.M.
AU - Milaneschi, Yusplitri
AU - Nivard, Michel
AU - Peyrot, Wouter J
AU - Posthuma, Danielle
AU - Willemsen, Gonneke
N1 - Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
PY - 2019/8/5
Y1 - 2019/8/5
N2 - 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.
AB - 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.
U2 - 10.1016/j.biopsych.2019.06.031
DO - 10.1016/j.biopsych.2019.06.031
M3 - Article
SP - 1
EP - 12
JO - Biological Psychiatry
JF - Biological Psychiatry
SN - 0006-3223
ER -