Abstract
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 (1.53â3.14), P=1.9 Ă 10-5). Two polymorphisms at 6p21.2 LINC00951âLRFN2 gene region were replicated in a separate data set, and rs4714329 reached genome-wide significance (OR=1.59 (1.37â1.85), P=1.6 Ă 10â9) in the meta-analysis. The risk allele also associated with antisocial features in the general population conditioned for severe problems in childhood family (ÎČ=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.
Highlights
Antisocial personality disorder (ASPD) is a life-long condition involving habitual irresponsible and delinquent behavior, with prevalence of 1â3% in the general population, and 40â70% in prison populations.[1,2,3,4,5] Previous twin and adoption studies report heritability estimates for ASPD up to 50%,6,7 and several studies have attempted to unravel the genetic background of antisocial personality
All of and TRG1 mRNAs in cerebellum and of TDRG1 in occipital cortex. the 22 items gave consistent odds ratio (OR), indicating that the original signal covers all the different aspects of ASPD according to DSM-. The results from this first genome-wide association study (GWAS) on ASPD reveal genome-wide significant and replicable associations for variants residing on IV, supporting the homogeneity of the study sample
According to our linkage investigation, our best hit, rs4714329 is in considerable LD with several polymorphisms of the LINC00951 gene, and not up to the same level with the very logical for different frontal cortex genetic regulation, but it may reflect those in cerebellum
Summary
Antisocial personality disorder (ASPD) is a life-long condition involving habitual irresponsible and delinquent behavior, with prevalence of 1â3% in the general population, and 40â70% in prison populations.[1,2,3,4,5] Previous twin and adoption studies report heritability estimates for ASPD up to 50%,6,7 and several studies have attempted to unravel the genetic background of antisocial personality. Men have consistently been found more often antisocial than women, it has been suggested that antisocial personality emerges from the same familial (including genetic and environmental factors) and non-familial influences in both sexes.[8] Conduct disorder prior to age 15 is an essential diagnostic criterion for ASPD, and it markedly increases the risk for ASPD in adulthood.[9] In a recent genome-wide association study (GWAS), Dick et al.[10] found several markers with genome-wide significance associated with conduct disorder symptomatology, especially in the gene C1QTNF7, none remained significant when individuals were classified dichotomously as cases and controls. Attention-deficit/hyperactivity disorder (ADHD) increases the risk for ASPD,[11] and genes that have been previously found in association with ADHD have been tested for association with
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