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

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. * Simon Rasmussen simon.rasmussen@cpr.ku. dk * Wesley K. Thompson wkthompson@ucsd.edu 1 Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark 2 iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Copenhagen, Denmark 3 Mental Health Centre Copenhagen, University of Copenhagen Hospital, Copenhagen, Denmark 4 Department of Bio and Health Informatics, Technical University of Denmark, Kongens Lyngby, Denmark 5 Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark 6 Department of Biomedicine, Aarhus University and Centre for Integrative Sequencing, iSEQ, Aarhus, Denmark 7 Aarhus Genome Center, Aarhus, Denmark 8 Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA 9 Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark 10 Psychosis Research Unit, Aarhus University Hospital, Risskov, Denmark 11 National Center for Register-Based Research, Aarhus University, Aarhus, Denmark 12 Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark 13 Department of Family Medicine and Public Health, Division of Biostatistics, University of California, San Diego, CA, USA Supplementary information The online version of this article (https:// doi.org/10.1038/s41431-019-0402-9) contains supplementary material, which is available to authorized users. 12 34 56 78 90 () ;,: 12 34 56 78 90 (); ,: