Immunity and mental illness: findings from a Danish population-based immunogenetic study of seven psychiatric and neurodevelopmental disorders

Ron Nudel, Michael E. Benros, Morten Dybdahl Krebs, Rosa Lundbye Allesøe, Camilla Koldbæk Lemvigh, Jonas Bybjerg-Grauholm, Anders D. Børglum, Mark J. Daly, Merete Nordentoft, Ole Mors, David M. Hougaard, Preben Bo Mortensen, Alfonso Buil, Thomas Werge, Simon Rasmussen*, Wesley K Thompson

*Corresponding author for this work

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Abstract

Human leukocyte antigen (HLA) genes encode proteins with important roles in the regulation of the immune system. Many studies have also implicated HLA genes in psychiatric and neurodevelopmental disorders. However, these studies usually focus on one disorder and/or on one HLA candidate gene, often with small samples. Here, we access a large dataset of 65,534 genotyped individuals consisting of controls (N = 19,645) and cases having one or more of autism spectrum disorder (N = 12,331), attention deficit hyperactivity disorder (N = 14,397), schizophrenia (N = 2401), bipolar disorder (N = 1391), depression (N = 18,511), anorexia (N = 2551) or intellectual disability (N = 3175). We imputed participants' HLA alleles to investigate the involvement of HLA genes in these disorders using regression models. We found a pronounced protective effect of DPB1*1501 on susceptibility to autism (p = 0.0094, OR = 0.72) and intellectual disability (p = 0.00099, OR = 0.41), with an increased protective effect on a comorbid diagnosis of both disorders (p = 0.003, OR = 0.29). We also identified a risk allele for intellectual disability, B*5701 (p = 0.00016, OR = 1.33). Associations with both alleles survived FDR correction and a permutation procedure. We did not find significant evidence for replication of previously-reported associations for autism or schizophrenia. Our results support an implication of HLA genes in autism and intellectual disability, which requires replication by other studies. Our study also highlights the importance of large sample sizes in HLA association studies.
Original languageEnglish
JournalEuropean journal of human genetics
Volume27
Pages (from-to)1445–1455
ISSN1018-4813
DOIs
Publication statusPublished - 2019

Bibliographical note

© The Author(s) 2019. This article is published with open access

Cite this

Nudel, Ron ; Benros, Michael E. ; Krebs, Morten Dybdahl ; Allesøe, Rosa Lundbye ; Lemvigh, Camilla Koldbæk ; Bybjerg-Grauholm, Jonas ; Børglum, Anders D. ; Daly, Mark J. ; Nordentoft, Merete ; Mors, Ole ; Hougaard, David M. ; Mortensen, Preben Bo ; Buil, Alfonso ; Werge, Thomas ; Rasmussen, Simon ; Thompson, Wesley K. / Immunity and mental illness: findings from a Danish population-based immunogenetic study of seven psychiatric and neurodevelopmental disorders. In: European journal of human genetics. 2019 ; Vol. 27. pp. 1445–1455.
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title = "Immunity and mental illness: findings from a Danish population-based immunogenetic study of seven psychiatric and neurodevelopmental disorders",
abstract = "Human leukocyte antigen (HLA) genes encode proteins with important roles in the regulation of the immune system. Many studies have also implicated HLA genes in psychiatric and neurodevelopmental disorders. However, these studies usually focus on one disorder and/or on one HLA candidate gene, often with small samples. Here, we access a large dataset of 65,534 genotyped individuals consisting of controls (N = 19,645) and cases having one or more of autism spectrum disorder (N = 12,331), attention deficit hyperactivity disorder (N = 14,397), schizophrenia (N = 2401), bipolar disorder (N = 1391), depression (N = 18,511), anorexia (N = 2551) or intellectual disability (N = 3175). We imputed participants' HLA alleles to investigate the involvement of HLA genes in these disorders using regression models. We found a pronounced protective effect of DPB1*1501 on susceptibility to autism (p = 0.0094, OR = 0.72) and intellectual disability (p = 0.00099, OR = 0.41), with an increased protective effect on a comorbid diagnosis of both disorders (p = 0.003, OR = 0.29). We also identified a risk allele for intellectual disability, B*5701 (p = 0.00016, OR = 1.33). Associations with both alleles survived FDR correction and a permutation procedure. We did not find significant evidence for replication of previously-reported associations for autism or schizophrenia. Our results support an implication of HLA genes in autism and intellectual disability, which requires replication by other studies. Our study also highlights the importance of large sample sizes in HLA association studies.",
author = "Ron Nudel and Benros, {Michael E.} and Krebs, {Morten Dybdahl} and Alles{\o}e, {Rosa Lundbye} and Lemvigh, {Camilla Koldb{\ae}k} and Jonas Bybjerg-Grauholm and B{\o}rglum, {Anders D.} and Daly, {Mark J.} and Merete Nordentoft and Ole Mors and Hougaard, {David M.} and Mortensen, {Preben Bo} and Alfonso Buil and Thomas Werge and Simon Rasmussen and Thompson, {Wesley K}",
note = "{\circledC} The Author(s) 2019. This article is published with open access",
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Nudel, R, Benros, ME, Krebs, MD, Allesøe, RL, Lemvigh, CK, Bybjerg-Grauholm, J, Børglum, AD, Daly, MJ, Nordentoft, M, Mors, O, Hougaard, DM, Mortensen, PB, Buil, A, Werge, T, Rasmussen, S & Thompson, WK 2019, 'Immunity and mental illness: findings from a Danish population-based immunogenetic study of seven psychiatric and neurodevelopmental disorders', European journal of human genetics, vol. 27, pp. 1445–1455. https://doi.org/10.1038/s41431-019-0402-9

Immunity and mental illness: findings from a Danish population-based immunogenetic study of seven psychiatric and neurodevelopmental disorders. / Nudel, Ron; Benros, Michael E.; Krebs, Morten Dybdahl; Allesøe, Rosa Lundbye; Lemvigh, Camilla Koldbæk; Bybjerg-Grauholm, Jonas; Børglum, Anders D.; Daly, Mark J.; Nordentoft, Merete; Mors, Ole; Hougaard, David M.; Mortensen, Preben Bo; Buil, Alfonso; Werge, Thomas; Rasmussen, Simon; Thompson, Wesley K.

In: European journal of human genetics, Vol. 27, 2019, p. 1445–1455.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Immunity and mental illness: findings from a Danish population-based immunogenetic study of seven psychiatric and neurodevelopmental disorders

AU - Nudel, Ron

AU - Benros, Michael E.

AU - Krebs, Morten Dybdahl

AU - Allesøe, Rosa Lundbye

AU - Lemvigh, Camilla Koldbæk

AU - Bybjerg-Grauholm, Jonas

AU - Børglum, Anders D.

AU - Daly, Mark J.

AU - Nordentoft, Merete

AU - Mors, Ole

AU - Hougaard, David M.

AU - Mortensen, Preben Bo

AU - Buil, Alfonso

AU - Werge, Thomas

AU - Rasmussen, Simon

AU - Thompson, Wesley K

N1 - © The Author(s) 2019. This article is published with open access

PY - 2019

Y1 - 2019

N2 - Human leukocyte antigen (HLA) genes encode proteins with important roles in the regulation of the immune system. Many studies have also implicated HLA genes in psychiatric and neurodevelopmental disorders. However, these studies usually focus on one disorder and/or on one HLA candidate gene, often with small samples. Here, we access a large dataset of 65,534 genotyped individuals consisting of controls (N = 19,645) and cases having one or more of autism spectrum disorder (N = 12,331), attention deficit hyperactivity disorder (N = 14,397), schizophrenia (N = 2401), bipolar disorder (N = 1391), depression (N = 18,511), anorexia (N = 2551) or intellectual disability (N = 3175). We imputed participants' HLA alleles to investigate the involvement of HLA genes in these disorders using regression models. We found a pronounced protective effect of DPB1*1501 on susceptibility to autism (p = 0.0094, OR = 0.72) and intellectual disability (p = 0.00099, OR = 0.41), with an increased protective effect on a comorbid diagnosis of both disorders (p = 0.003, OR = 0.29). We also identified a risk allele for intellectual disability, B*5701 (p = 0.00016, OR = 1.33). Associations with both alleles survived FDR correction and a permutation procedure. We did not find significant evidence for replication of previously-reported associations for autism or schizophrenia. Our results support an implication of HLA genes in autism and intellectual disability, which requires replication by other studies. Our study also highlights the importance of large sample sizes in HLA association studies.

AB - Human leukocyte antigen (HLA) genes encode proteins with important roles in the regulation of the immune system. Many studies have also implicated HLA genes in psychiatric and neurodevelopmental disorders. However, these studies usually focus on one disorder and/or on one HLA candidate gene, often with small samples. Here, we access a large dataset of 65,534 genotyped individuals consisting of controls (N = 19,645) and cases having one or more of autism spectrum disorder (N = 12,331), attention deficit hyperactivity disorder (N = 14,397), schizophrenia (N = 2401), bipolar disorder (N = 1391), depression (N = 18,511), anorexia (N = 2551) or intellectual disability (N = 3175). We imputed participants' HLA alleles to investigate the involvement of HLA genes in these disorders using regression models. We found a pronounced protective effect of DPB1*1501 on susceptibility to autism (p = 0.0094, OR = 0.72) and intellectual disability (p = 0.00099, OR = 0.41), with an increased protective effect on a comorbid diagnosis of both disorders (p = 0.003, OR = 0.29). We also identified a risk allele for intellectual disability, B*5701 (p = 0.00016, OR = 1.33). Associations with both alleles survived FDR correction and a permutation procedure. We did not find significant evidence for replication of previously-reported associations for autism or schizophrenia. Our results support an implication of HLA genes in autism and intellectual disability, which requires replication by other studies. Our study also highlights the importance of large sample sizes in HLA association studies.

U2 - 10.1038/s41431-019-0402-9

DO - 10.1038/s41431-019-0402-9

M3 - Journal article

VL - 27

SP - 1445

EP - 1455

JO - European Journal of Human Genetics

JF - European Journal of Human Genetics

SN - 1018-4813

ER -