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

Kylie P. Glanville; Jonathan R. I. Coleman; Ken B. Hanscombe; Jack Euesden; Shing Wan Choi; Kirstin Purves; Gerome Breen; Tracy M. Air; Till M. F. 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; Eco J. C. de Geus; Hans Joergen Grabe; Steven P. Hamilton; Ian Jones; Lisa A. Jones; James A. Knowles; Zoltan Kutalik; Douglas F. Levinson; Glyn Lewis; Penelope A. Lind; Susanne Lucae; Susanne Lucae; Patrick K.E. Magnusson.; Peter McGuffin; Andrew McIntosh; Yuri Milaneschi; Cathryn M. Lewis; Sara Mostafavi; Bertram Muller-Myhsok; Nancy L. Pedersen; Brenda W. Penninx; James B. Potash; Martin Preisig; Stephan Ripke; Jianxin Shi; Stanley I Shyn; Jordan W. Smoller; Fabian Streit; Patrick F. Sullivan; H Tiemeier; Rudolf Uher; Sandra Van der Auwera; Myrna M. Weissman; Paul F. O'Reilly; Cathryn M. Lewis

doi:10.1016/j.biopsych.2019.06.031

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

Kylie P. Glanville, Jonathan R. I. Coleman, Ken B. Hanscombe, Jack Euesden, Shing Wan Choi, Kirstin Purves, Gerome Breen, Tracy M. Air, Till M. F. 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, Eco J. C. de GeusHans Joergen Grabe, Steven P. Hamilton, Ian Jones, Lisa A. Jones, James A. Knowles, Zoltan Kutalik, Douglas F. Levinson, Glyn Lewis, Penelope A. Lind, Susanne Lucae, Susanne Lucae, Patrick K.E. Magnusson., Peter McGuffin, Andrew McIntosh, Yuri Milaneschi, Cathryn M. Lewis, Sara Mostafavi, Bertram Muller-Myhsok, Nancy L. Pedersen, Brenda W. Penninx, James B. Potash, Martin Preisig, Stephan Ripke, Jianxin Shi, Stanley I Shyn, Jordan W. Smoller, Fabian Streit, Patrick F. Sullivan, H Tiemeier, Rudolf Uher, Sandra Van der Auwera, Myrna M. Weissman, Paul F. O'Reilly, Cathryn M. Lewis

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Abstract

Background: The prevalence of depression is higher in individuals suffering from 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.

Method: We fine-mapped the classical MHC (chr6: 29.6-33.1 Mb), imputing 216 Human Leukocyte Antigen (HLA) alleles and four Complement Component 4 (C4) haplotypes in studies from the Psychiatric Genomics Consortium (PGC) Major Depressive Disorder (MDD) working group and the UK Biobank (UKB). 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-e6) and a candidate threshold (1.6e-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% CI = 0.97-0.99).

Discussion: 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 are either rare or have very modest effect sizes.

Original language	English
Pages (from-to)	419-430
Number of pages	12
Journal	Biological psychiatry
Volume	87
Issue number	5
Early online date	5 Aug 2019
DOIs	https://doi.org/10.1016/j.biopsych.2019.06.031
Publication status	Published - 1 Mar 2020

Keywords

Autoimmune disorder
Complement
Genetic association
Human leukocyte antigen
Major depressive disorder
Major histocompatibility complex

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Glanville, K. P., Coleman, J. R. I., Hanscombe, K. B., Euesden, J., Choi, S. W., Purves, K., Breen, G., Air, T. M., Andlauer, T. M. F., Baune, B. T., Binder, E. B., Blackwood, D. H. R., Boomsma, D. I., Buttenschøn, H. N., Colodro-Conde, L., Dannlowski, U., Direk, N., Dunn, E. C., Forstner, A. J., ... Lewis, C. M. (2020). Classical Human Leukocyte Antigen Alleles and C4 Haplotypes Are Not Significantly Associated With Depression. Biological psychiatry, 87(5), 419-430. https://doi.org/10.1016/j.biopsych.2019.06.031

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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 suffering from 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. Method: We fine-mapped the classical MHC (chr6: 29.6-33.1 Mb), imputing 216 Human Leukocyte Antigen (HLA) alleles and four Complement Component 4 (C4) haplotypes in studies from the Psychiatric Genomics Consortium (PGC) Major Depressive Disorder (MDD) working group and the UK Biobank (UKB). 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-e6) and a candidate threshold (1.6e-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% CI = 0.97-0.99).Discussion: 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 are either rare or have very modest effect sizes. ",

keywords = "Autoimmune disorder, Complement, Genetic association, Human leukocyte antigen, Major depressive disorder, Major histocompatibility complex",

author = "Glanville, {Kylie P.} and Coleman, {Jonathan R. I.} and Hanscombe, {Ken B.} and Jack Euesden and Choi, {Shing Wan} and Kirstin Purves and Gerome Breen and Air, {Tracy M.} and Andlauer, {Till M. F.} 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 Joergen} and Hamilton, {Steven P.} and Ian Jones and Jones, {Lisa A.} and Knowles, {James A.} and Zoltan Kutalik and Levinson, {Douglas F.} and Glyn Lewis and Lind, {Penelope A.} and Susanne Lucae and Susanne Lucae and Magnusson., {Patrick K.E.} and Peter McGuffin and Andrew McIntosh and Yuri Milaneschi and Lewis, {Cathryn M.} and Sara Mostafavi and Bertram Muller-Myhsok and Pedersen, {Nancy L.} and Penninx, {Brenda W.} and Potash, {James B.} and Martin Preisig and Stephan Ripke and Jianxin Shi and Shyn, {Stanley I} and Smoller, {Jordan W.} and Fabian Streit and Sullivan, {Patrick F.} and H Tiemeier and Rudolf Uher and {der Auwera}, {Sandra Van} and Weissman, {Myrna M.} and O'Reilly, {Paul F.} and Lewis, {Cathryn M.}",

year = "2020",

month = mar,

day = "1",

doi = "10.1016/j.biopsych.2019.06.031",

language = "English",

volume = "87",

pages = "419--430",

journal = "Biological psychiatry",

issn = "0006-3223",

publisher = "Elsevier",

number = "5",

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Glanville, KP , Coleman, JRI, Hanscombe, KB, Euesden, J, Choi, SW , Purves, K , Breen, G, Air, TM, Andlauer, TMF, 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, Lucae, S, Magnusson., PKE, McGuffin, P, McIntosh, A, Milaneschi, Y, Lewis, CM, Mostafavi, S, Muller-Myhsok, B, Pedersen, NL, Penninx, BW, Potash, JB, Preisig, M, Ripke, S, Shi, J, Shyn, SI, Smoller, JW, Streit, F, Sullivan, PF, Tiemeier, H, Uher, R, der Auwera, SV, Weissman, MM, O'Reilly, PF & Lewis, CM 2020, 'Classical Human Leukocyte Antigen Alleles and C4 Haplotypes Are Not Significantly Associated With Depression', Biological psychiatry, vol. 87, no. 5, pp. 419-430. https://doi.org/10.1016/j.biopsych.2019.06.031

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

AU - Breen, Gerome

AU - Air, Tracy M.

AU - Andlauer, Till M. F.

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 Joergen

AU - Hamilton, Steven P.

AU - Jones, Ian

AU - Jones, Lisa A.

AU - Knowles, James A.

AU - Kutalik, Zoltan

AU - Levinson, Douglas F.

AU - Lewis, Glyn

AU - Lind, Penelope A.

AU - Lucae, Susanne

AU - Magnusson., Patrick K.E.

AU - McGuffin, Peter

AU - McIntosh, Andrew

AU - Milaneschi, Yuri

AU - Lewis, Cathryn M.

AU - Mostafavi, Sara

AU - Muller-Myhsok, Bertram

AU - Pedersen, Nancy L.

AU - Penninx, Brenda W.

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, H

AU - Uher, Rudolf

AU - der Auwera, Sandra Van

AU - Weissman, Myrna M.

AU - O'Reilly, Paul F.

AU - Lewis, Cathryn M.

PY - 2020/3/1

Y1 - 2020/3/1

N2 - Background: The prevalence of depression is higher in individuals suffering from 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. Method: We fine-mapped the classical MHC (chr6: 29.6-33.1 Mb), imputing 216 Human Leukocyte Antigen (HLA) alleles and four Complement Component 4 (C4) haplotypes in studies from the Psychiatric Genomics Consortium (PGC) Major Depressive Disorder (MDD) working group and the UK Biobank (UKB). 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-e6) and a candidate threshold (1.6e-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% CI = 0.97-0.99).Discussion: 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 are either rare or have very modest effect sizes.

AB - Background: The prevalence of depression is higher in individuals suffering from 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. Method: We fine-mapped the classical MHC (chr6: 29.6-33.1 Mb), imputing 216 Human Leukocyte Antigen (HLA) alleles and four Complement Component 4 (C4) haplotypes in studies from the Psychiatric Genomics Consortium (PGC) Major Depressive Disorder (MDD) working group and the UK Biobank (UKB). 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-e6) and a candidate threshold (1.6e-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% CI = 0.97-0.99).Discussion: 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 are either rare or have very modest effect sizes.

KW - Autoimmune disorder

KW - Complement

KW - Genetic association

KW - Human leukocyte antigen

KW - Major depressive disorder

KW - Major histocompatibility complex

UR - http://www.scopus.com/inward/record.url?scp=85072749953&partnerID=8YFLogxK

U2 - 10.1016/j.biopsych.2019.06.031

DO - 10.1016/j.biopsych.2019.06.031

M3 - Article

SN - 0006-3223

VL - 87

SP - 419

EP - 430

JO - Biological psychiatry

JF - Biological psychiatry

IS - 5

ER -

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

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Keywords

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