Genome-wide association study of antisocial personality disorder.
The pathophysiology of antisocial personality disorder (ASPD) remains unclear. Although the most consistent biological finding is reduced grey matter volume in the frontal cortex, about 50% of the total liability to developing ASPD has been attributed to genetic factors. The contributing genes remain largely unknown. Therefore, we sought to study the genetic background of ASPD. We conducted a genome-wide association study (GWAS) and a replication analysis of Finnish criminal offenders fulfilling DSM-IV criteria for ASPD (N=370, N=5850 for controls, GWAS; N=173, N=3766 for controls and replication sample). The GWAS resulted in suggestive associations of two clusters of single-nucleotide polymorphisms at 6p21.2 and at 6p21.32 at the human leukocyte antigen (HLA) region. Imputation of HLA alleles revealed an independent association with DRB1*01:01 (odds ratio (OR)=2.19 (1.53-3.14), P=1.9 × 10(-5)). Two polymorphisms at 6p21.2 LINC00951-LRFN2 gene region were replicated in a separate data set, and rs4714329 reached genome-wide significance (OR=1.59 (1.37-1.85), P=1.6 × 10(-9)) in the meta-analysis. The risk allele also associated with antisocial features in the general population conditioned for severe problems in childhood family (β=0.68, P=0.012). Functional analysis in brain tissue in open access GTEx and Braineac databases revealed eQTL associations of rs4714329 with LINC00951 and LRFN2 in cerebellum. In humans, LINC00951 and LRFN2 are both expressed in the brain, especially in the frontal cortex, which is intriguing considering the role of the frontal cortex in behavior and the neuroanatomical findings of reduced gray matter volume in ASPD. To our knowledge, this is the first study showing genome-wide significant and replicable findings on genetic variants associated with any personality disorder.
National Institute for Health and Welfare, Department of Health, Helsinki, Finland.|Department of Forensic Psychiatry, Niuvanniemi Hospital, University of Eastern Finland, Kuopio, Finland.|Department of Psychiatry, University of Helsinki, Helsinki, Finland.|Department of Psychiatry, Helsinki University Hospital, Helsinki, Finland.
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Rautiainen
National Institute for Health and Welfare, Department of Health, Helsinki, Finland.|Department of Psychiatry, University of Helsinki, Helsinki, Finland.|Department of Psychiatry, Helsinki University Hospital, Helsinki, Finland.|Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
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Paunio
Department of Forensic Psychiatry, Niuvanniemi Hospital, University of Eastern Finland, Kuopio, Finland.
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Repo-Tiihonen
Department of Psychiatry, University of Helsinki, Helsinki, Finland.|Department of Psychiatry, Helsinki University Hospital, Helsinki, Finland.
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Virkkunen
National Institute for Health and Welfare, Department of Health, Helsinki, Finland.|Stanford University Center for Sleep Sciences, Palo Alto, CA, USA.
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HM
Ollila
National Institute for Health and Welfare, Department of Health, Helsinki, Finland.|Department of Psychiatry, University of Helsinki, Helsinki, Finland.|Department of Psychiatry, Helsinki University Hospital, Helsinki, Finland.
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Sulkava
Stanford University Center for Sleep Sciences, Palo Alto, CA, USA.
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Jolanki
Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.|Wellcome Trust Sanger Institute, Hinxton, UK.|Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.|Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
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Palotie
Department of Forensic Psychiatry, Niuvanniemi Hospital, University of Eastern Finland, Kuopio, Finland.|Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
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Tiihonen
D000328:Adult; D000987:Antisocial Personality Disorder / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000378:metabolism; D016022:Case-Control Studies; D015815:Cell Adhesion Molecules / Q000235:genetics; D002531:Cerebellum / Q000378:metabolism; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics*; D057237:Criminals; D005260:Female; D005387:Finland; D005625:Frontal Lobe / Q000378:metabolism; D055106:Genome-Wide Association Study; D066128:Gray Matter / Q000378:metabolism / Q000473:pathology; D006680:HLA Antigens / Q000235:genetics*; D059805:HLA-DR alpha-Chains / Q000235:genetics; D059811:HLA-DRB1 Chains / Q000235:genetics; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins; D016017:Odds Ratio; D009929:Organ Size; D020641:Polymorphism, Single Nucleotide; D062085:RNA, Long Noncoding / Q000235:genetics* / Q000378:metabolism
D015815:Cell Adhesion Molecules; D006680:HLA Antigens; D059805:HLA-DR alpha-Chains; D059811:HLA-DRB1 Chains; C487961:HLA-DRB1*01:01 antigen; C000621463:LRFN2 protein, human; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D062085:RNA, Long Noncoding; C493091:SDK1 protein, human