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

Kylie P. Glanville, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Jonathan R. I. Coleman, Ken B. Hanscombe, Jack Euesden, Shing Wan Choi, Kirstin L. Purves, Gerome Breen, Tracy M. Air, Till F. M. Andlauer, Bernhard T. Baune, Elisabeth B. Binder, Douglas H. R. Blackwood, Dorret I. Boomsma, Henriette N. Buttenschøn, Lucía Colodro-Conde, Udo Dannlowski, Nese Direk, Erin C. Dunn, Andreas J. Forstner & 33 others Eco J. C. de Geus, Hans J. Grabe, Steven P. Hamilton, Ian Jones, Lisa A. Jones, James A. Knowles, Zoltán Kutalik, Douglas F. Levinson, Glyn Lewis, Penelope A. Lind, Susanne Lucae, Patrik K. Magnusson, Peter McGuffin, Andrew M. McIntosh, Yuri Milaneschi, Ole Mors, Sara Mostafavi, Bertram Müller-Myhsok, Nancy L. Pedersen, Brenda W. J. H. Penninx, James B. Potash, Martin Preisig, Stephan Ripke, Aartjan T. F. Beekman, Rick Jansen, Christel M. Middeldorp, Wouter J. Peyrot, Danielle Posthuma, Robert Schoevers, Johannes H. Smit, E. J. C. de Geus, Myrna M. Weissman, Paul F. O'Reilly

Research output: Contribution to journalArticleAcademicpeer-review

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 languageEnglish
JournalBiological Psychiatry
DOIs
Publication statusE-pub ahead of print - 5 Aug 2019

Cite this

Glanville, K. P., Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Coleman, J. R. I., Hanscombe, K. B., Euesden, J., Choi, S. W., ... O'Reilly, P. F. (2019). Classical Human Leukocyte Antigen Alleles and C4 Haplotypes Are Not Significantly Associated With Depression. Biological Psychiatry. https://doi.org/10.1016/j.biopsych.2019.06.031
Glanville, Kylie P. ; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium ; Coleman, Jonathan R. I. ; Hanscombe, Ken B. ; Euesden, Jack ; Choi, Shing Wan ; Purves, Kirstin L. ; Breen, Gerome ; Air, Tracy M. ; Andlauer, Till F. M. ; Baune, Bernhard T. ; Binder, Elisabeth B. ; Blackwood, Douglas H. R. ; Boomsma, Dorret I. ; Buttenschøn, Henriette N. ; Colodro-Conde, Lucía ; Dannlowski, Udo ; Direk, Nese ; Dunn, Erin C. ; Forstner, Andreas J. ; de Geus, Eco J. C. ; Grabe, Hans J. ; Hamilton, Steven P. ; Jones, Ian ; Jones, Lisa A. ; Knowles, James A. ; Kutalik, Zoltán ; Levinson, Douglas F. ; Lewis, Glyn ; Lind, Penelope A. ; Lucae, Susanne ; Magnusson, Patrik K. ; McGuffin, Peter ; McIntosh, Andrew M. ; Milaneschi, Yuri ; Mors, Ole ; Mostafavi, Sara ; Müller-Myhsok, Bertram ; Pedersen, Nancy L. ; Penninx, Brenda W. J. H. ; Potash, James B. ; Preisig, Martin ; Ripke, Stephan ; Beekman, Aartjan T. F. ; Jansen, Rick ; Middeldorp, Christel M. ; Peyrot, Wouter J. ; Posthuma, Danielle ; Schoevers, Robert ; Smit, Johannes H. ; de Geus, E. J. C. ; Weissman, Myrna M. ; O'Reilly, Paul F. / Classical Human Leukocyte Antigen Alleles and C4 Haplotypes Are Not Significantly Associated With Depression. In: Biological Psychiatry. 2019.
@article{0b6f94f6de0a46efbf11fa80ff8b90cf,
title = "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.",
author = "Glanville, {Kylie P.} and {Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium} and Coleman, {Jonathan R. I.} and Hanscombe, {Ken B.} and Jack Euesden and Choi, {Shing Wan} and Purves, {Kirstin L.} and Gerome Breen and Air, {Tracy M.} and Andlauer, {Till F. M.} and Baune, {Bernhard T.} and Binder, {Elisabeth B.} and Blackwood, {Douglas H. R.} and Boomsma, {Dorret I.} and Buttensch{\o}n, {Henriette N.} and Luc{\'i}a Colodro-Conde and Udo Dannlowski and Nese Direk and Dunn, {Erin C.} and Forstner, {Andreas J.} and {de Geus}, {Eco J. C.} and Grabe, {Hans J.} and Hamilton, {Steven P.} and Ian Jones and Jones, {Lisa A.} and Knowles, {James A.} and Zolt{\'a}n Kutalik and Levinson, {Douglas F.} and Glyn Lewis and Lind, {Penelope A.} and Susanne Lucae and Magnusson, {Patrik K.} and Peter McGuffin and McIntosh, {Andrew M.} and Yuri Milaneschi and Ole Mors and Sara Mostafavi and Bertram M{\"u}ller-Myhsok and Pedersen, {Nancy L.} and Penninx, {Brenda W. J. H.} and Potash, {James B.} and Martin Preisig and Stephan Ripke and Beekman, {Aartjan T. F.} and Rick Jansen and Middeldorp, {Christel M.} and Peyrot, {Wouter J.} and Danielle Posthuma and Robert Schoevers and Smit, {Johannes H.} and {de Geus}, {E. J. C.} and Weissman, {Myrna M.} and O'Reilly, {Paul F.}",
year = "2019",
month = "8",
day = "5",
doi = "10.1016/j.biopsych.2019.06.031",
language = "English",
journal = "Biological Psychiatry",
issn = "0006-3223",
publisher = "Elsevier USA",

}

Glanville, KP, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Coleman, JRI, Hanscombe, KB, Euesden, J, Choi, SW, Purves, KL, Breen, G, Air, TM, Andlauer, TFM, Baune, BT, Binder, EB, Blackwood, DHR, Boomsma, DI, Buttenschøn, HN, Colodro-Conde, L, Dannlowski, U, Direk, N, Dunn, EC, Forstner, AJ, de Geus, EJC, Grabe, HJ, Hamilton, SP, Jones, I, Jones, LA, Knowles, JA, Kutalik, Z, Levinson, DF, Lewis, G, Lind, PA, Lucae, S, Magnusson, PK, McGuffin, P, McIntosh, AM, Milaneschi, Y, Mors, O, Mostafavi, S, Müller-Myhsok, B, Pedersen, NL, Penninx, BWJH, Potash, JB, Preisig, M, Ripke, S, Beekman, ATF, Jansen, R, Middeldorp, CM, Peyrot, WJ, Posthuma, D, Schoevers, R, Smit, JH, de Geus, EJC, Weissman, MM & O'Reilly, PF 2019, 'Classical Human Leukocyte Antigen Alleles and C4 Haplotypes Are Not Significantly Associated With Depression' Biological Psychiatry. https://doi.org/10.1016/j.biopsych.2019.06.031

Classical Human Leukocyte Antigen Alleles and C4 Haplotypes Are Not Significantly Associated With Depression. / Glanville, Kylie P.; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium; Coleman, Jonathan R. I.; Hanscombe, Ken B.; Euesden, Jack; Choi, Shing Wan; Purves, Kirstin L.; Breen, Gerome; Air, Tracy M.; Andlauer, Till F. M.; Baune, Bernhard T.; Binder, Elisabeth B.; Blackwood, Douglas H. R.; Boomsma, Dorret I.; Buttenschøn, Henriette N.; Colodro-Conde, Lucía; Dannlowski, Udo; Direk, Nese; Dunn, Erin C.; Forstner, Andreas J.; de Geus, Eco J. C.; Grabe, Hans J.; Hamilton, Steven P.; Jones, Ian; Jones, Lisa A.; Knowles, James A.; Kutalik, Zoltán; Levinson, Douglas F.; Lewis, Glyn; Lind, Penelope A.; Lucae, Susanne; Magnusson, Patrik K.; McGuffin, Peter; McIntosh, Andrew M.; Milaneschi, Yuri; Mors, Ole; Mostafavi, Sara; Müller-Myhsok, Bertram; Pedersen, Nancy L.; Penninx, Brenda W. J. H.; Potash, James B.; Preisig, Martin; Ripke, Stephan; Beekman, Aartjan T. F.; Jansen, Rick; Middeldorp, Christel M.; Peyrot, Wouter J.; Posthuma, Danielle; Schoevers, Robert; Smit, Johannes H.; de Geus, E. J. C.; Weissman, Myrna M.; O'Reilly, Paul F.

In: Biological Psychiatry, 05.08.2019.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Classical Human Leukocyte Antigen Alleles and C4 Haplotypes Are Not Significantly Associated With Depression

AU - Glanville, Kylie P.

AU - Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium

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 - Beekman, Aartjan T. F.

AU - Jansen, Rick

AU - Middeldorp, Christel M.

AU - Peyrot, Wouter J.

AU - Posthuma, Danielle

AU - Schoevers, Robert

AU - Smit, Johannes H.

AU - de Geus, E. J. C.

AU - Weissman, Myrna M.

AU - O'Reilly, Paul F.

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.

UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85072749953&origin=inward

UR - https://www.ncbi.nlm.nih.gov/pubmed/31570195

U2 - 10.1016/j.biopsych.2019.06.031

DO - 10.1016/j.biopsych.2019.06.031

M3 - Article

JO - Biological Psychiatry

JF - Biological Psychiatry

SN - 0006-3223

ER -

Glanville KP, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Coleman JRI, Hanscombe KB, Euesden J, Choi SW et al. Classical Human Leukocyte Antigen Alleles and C4 Haplotypes Are Not Significantly Associated With Depression. Biological Psychiatry. 2019 Aug 5. https://doi.org/10.1016/j.biopsych.2019.06.031