PMID- 30976114 OWN - NLM STAT- MEDLINE DCOM- 20200612 LR - 20240214 IS - 1476-5438 (Electronic) IS - 1018-4813 (Print) IS - 1018-4813 (Linking) VI - 27 IP - 9 DP - 2019 Sep TI - Immunity and mental illness: findings from a Danish population-based immunogenetic study of seven psychiatric and neurodevelopmental disorders. PG - 1445-1455 LID - 10.1038/s41431-019-0402-9 [doi] 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. FAU - Nudel, Ron AU - Nudel R AUID- ORCID: 0000-0003-2309-011X AD - Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark. AD - iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Copenhagen, Denmark. FAU - Benros, Michael E AU - Benros ME AD - iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Copenhagen, Denmark. AD - Mental Health Centre Copenhagen, University of Copenhagen Hospital, Copenhagen, Denmark. FAU - Krebs, Morten Dybdahl AU - Krebs MD AD - Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark. AD - iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Copenhagen, Denmark. FAU - Allesoe, Rosa Lundbye AU - Allesoe RL AD - Department of Bio and Health Informatics, Technical University of Denmark, Kongens Lyngby, Denmark. FAU - Lemvigh, Camilla Koldbaek AU - Lemvigh CK AD - Department of Bio and Health Informatics, Technical University of Denmark, Kongens Lyngby, Denmark. FAU - Bybjerg-Grauholm, Jonas AU - Bybjerg-Grauholm J AUID- ORCID: 0000-0003-1705-4008 AD - iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Copenhagen, Denmark. AD - Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark. FAU - Borglum, Anders D AU - Borglum AD AD - iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Copenhagen, Denmark. AD - Department of Biomedicine, Aarhus University and Centre for Integrative Sequencing, iSEQ, Aarhus, Denmark. AD - Aarhus Genome Center, Aarhus, Denmark. FAU - Daly, Mark J AU - Daly MJ AUID- ORCID: 0000-0002-0949-8752 AD - Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA. FAU - Nordentoft, Merete AU - Nordentoft M AD - iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Copenhagen, Denmark. AD - Mental Health Centre Copenhagen, University of Copenhagen Hospital, Copenhagen, Denmark. AD - Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. FAU - Mors, Ole AU - Mors O AD - iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Copenhagen, Denmark. AD - Psychosis Research Unit, Aarhus University Hospital, Risskov, Denmark. FAU - Hougaard, David M AU - Hougaard DM AD - iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Copenhagen, Denmark. AD - Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark. FAU - Mortensen, Preben Bo AU - Mortensen PB AD - iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Copenhagen, Denmark. AD - National Center for Register-Based Research, Aarhus University, Aarhus, Denmark. FAU - Buil, Alfonso AU - Buil A AD - Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark. AD - iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Copenhagen, Denmark. FAU - Werge, Thomas AU - Werge T AD - Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark. AD - iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Copenhagen, Denmark. AD - Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. FAU - Rasmussen, Simon AU - Rasmussen S AD - Department of Bio and Health Informatics, Technical University of Denmark, Kongens Lyngby, Denmark. simon.rasmussen@cpr.ku.dk. AD - Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. simon.rasmussen@cpr.ku.dk. FAU - Thompson, Wesley K AU - Thompson WK AD - Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark. wkthompson@ucsd.edu. AD - iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Copenhagen, Denmark. wkthompson@ucsd.edu. AD - Department of Family Medicine and Public Health, Division of Biostatistics, University of California, San Diego, CA, USA. wkthompson@ucsd.edu. LA - eng GR - R01 GM104400/GM/NIGMS NIH HHS/United States GR - U01 MH094432/MH/NIMH NIH HHS/United States GR - U01 MH109536/MH/NIMH NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20190411 PL - England TA - Eur J Hum Genet JT - European journal of human genetics : EJHG JID - 9302235 RN - 0 (HLA Antigens) SB - IM EIN - Eur J Hum Genet. 2021 Aug;29(8):1316. PMID: 33293699 MH - Alleles MH - Denmark/epidemiology MH - Disease Susceptibility/*immunology MH - Exome MH - Genetic Predisposition to Disease MH - Genetic Testing MH - HLA Antigens/genetics MH - Humans MH - Immunogenetics MH - Mental Disorders/diagnosis/epidemiology/*etiology MH - Neurodevelopmental Disorders/diagnosis/epidemiology/genetics/immunology MH - Polymorphism, Single Nucleotide MH - Population Surveillance PMC - PMC6777475 COIS- All researchers had full independence from the funders. The authors declare that they have no conflict of interest. EDAT- 2019/04/13 06:00 MHDA- 2020/06/13 06:00 PMCR- 2019/04/11 CRDT- 2019/04/13 06:00 PHST- 2018/08/14 00:00 [received] PHST- 2019/03/19 00:00 [accepted] PHST- 2019/03/11 00:00 [revised] PHST- 2019/04/13 06:00 [pubmed] PHST- 2020/06/13 06:00 [medline] PHST- 2019/04/13 06:00 [entrez] PHST- 2019/04/11 00:00 [pmc-release] AID - 10.1038/s41431-019-0402-9 [pii] AID - 402 [pii] AID - 10.1038/s41431-019-0402-9 [doi] PST - ppublish SO - Eur J Hum Genet. 2019 Sep;27(9):1445-1455. doi: 10.1038/s41431-019-0402-9. Epub 2019 Apr 11.