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 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; 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; Jianxin Shi; Stanley I Shyn; Jordan W Smoller; Fabian Streit; Patrick F Sullivan; Henning Tiemeier; Rudolf Uher; Sandra Van der Auwera; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium; Thomas Mears Werge; Thomas Folkmann Hansen

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 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, Eco J C de GeusHans 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, Jianxin Shi, Stanley I Shyn, Jordan W Smoller, Fabian Streit, Patrick F Sullivan, Henning Tiemeier, Rudolf Uher, Sandra Van der Auwera, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Thomas Mears Werge, Thomas Folkmann Hansen

21 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Biological Psychiatry
Vol/bind	87
Udgave nummer	5
Sider (fra-til)	419-430
Antal sider	12
ISSN	0006-3223
DOI	https://doi.org/10.1016/j.biopsych.2019.06.031
Status	Udgivet - 1 mar. 2020

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10.1016/j.biopsych.2019.06.031

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Glanville, K. P., Coleman, J. R. I., Hanscombe, K. B., Euesden, J., Choi, S. W., Purves, K. L., Breen, G., Air, T. M., Andlauer, T. F. M., 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., ... Hansen, T. F. (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

Glanville, KP, 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, Shi, J, Shyn, SI, Smoller, JW, Streit, F, Sullivan, PF, Tiemeier, H, Uher, R, Van der Auwera, S, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Werge, TM & Hansen, TF 2020, 'Classical Human Leukocyte Antigen Alleles and C4 Haplotypes Are Not Significantly Associated With Depression', Biological Psychiatry, bind 87, nr. 5, s. 419-430. https://doi.org/10.1016/j.biopsych.2019.06.031

@article{0e0f1aa46c364620a81274c1c9b0e6af,

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.",

keywords = "Alleles, Autoimmune disorder, Complement, Depression, Depressive Disorder, Major/epidemiology, Genetic Predisposition to Disease, Genetic association, HLA Antigens, Haplotypes, Human leukocyte antigen, Humans, Major Histocompatibility Complex, Major depressive disorder, Major histoconnpatibility complex, Major histocompatibility complex",

author = "Glanville, {Kylie P} 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 Jianxin Shi and Shyn, {Stanley I} and Smoller, {Jordan W} and Fabian Streit and Sullivan, {Patrick F} and Henning Tiemeier and Rudolf Uher and {Van der Auwera}, Sandra and {Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium} and Werge, {Thomas Mears} and Hansen, {Thomas Folkmann}",

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 Inc",

number = "5",

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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 - Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium

AU - Werge, Thomas Mears

AU - Hansen, Thomas Folkmann

PY - 2020/3/1

Y1 - 2020/3/1

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.

KW - Alleles

KW - Autoimmune disorder

KW - Complement

KW - Depression

KW - Depressive Disorder, Major/epidemiology

KW - Genetic Predisposition to Disease

KW - Genetic association

KW - HLA Antigens

KW - Haplotypes

KW - Human leukocyte antigen

KW - Humans

KW - Major Histocompatibility Complex

KW - Major depressive disorder

KW - Major histoconnpatibility complex

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 - Journal article

C2 - 31570195

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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