Genome-wide association study of antisocial personality disorder.
paper
Cited
Public
- Authors
- Rautiainen, M-R; Paunio, T; Repo-Tiihonen, E; Virkkunen, M; Ollila, H M; Sulkava, S; Jolanki, O; Palotie, A; Tiihonen, J
- Year
- 2016
- Journal
- Translational psychiatry
- PMID
- 27598967
- DOI
- 10.1038/tp.2016.155
- PMCID
- PMC5048197
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 Γ 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 Γ 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 (Ξ²=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.
The flow-chart of the study. Box (a) illustrates the GWAS analyses including 370 cases (339 males, 31 females) and 5850 controls (3345 males, 2505 females) from the GenMets (sub sample of Health 2000 study) and Corogene (sub sample of FINRISK study) control samples. (b) On the basis of the GWAS results, eight variants were selected for analyses in the replication sample composed of those CRIME cases (N=173, 141 males, 32 females) and Health 2000 controls (N=3766, 1587 males, 2179 females) that were not included in the GWAS analyses. (c) The eight replication variants were included in the meta-analyses of the GWAS sample and the replication sample, including altogether 543 cases and 9616 controls. (d) The most significant hit of the analyses, rs4714329, was analyzed in the population sample for the association with antisocial features (N=4944, 2211 males, 2733 females), and for the gene x environment interaction of antisocial features and childhood adverse environment (N=1536, 636 males, 900 females). GWAS, genome-wide association studies. HLA, human leukocyte antigen; LD, linkage disequalibrium; MAF, minor allele frequency.
Manhattan plot of the entire sample of males and females combined in the analysis of the ASPD cases versus population-based controls (a) and for the males' sub-sample (b). ASPD, antisocial personality disorder.
Association peaks at the chr 6 LINC00951 (a) and HLA (b) regions. Extended LD over the HLA class II region can be observed in b. HLA, human leukocyte antigen; LD, linkage disequalibrium; SNP, single nucleotide polymorphism.
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