Genome-wide association data suggest ABCB1 and immune-related gene sets may be involved in adult antisocial behavior.
paper
Primary
Public
- Authors
- Salvatore, J E; Edwards, A C; McClintick, J N; Bigdeli, T B; Adkins, A; Aliev, F; Edenberg, H J; Foroud, T; Hesselbrock, V; Kramer, J; Nurnberger, J I; Schuckit, M; Tischfield, J A; Xuei, X; Dick, D M
- Year
- 2015
- Journal
- Translational psychiatry
- PMID
- 25918995
- DOI
- 10.1038/tp.2015.36
- PMCID
- PMC4462601
Adult antisocial behavior (AAB) is moderately heritable, relatively common and has adverse consequences for individuals and society. We examined the molecular genetic basis of AAB in 1379 participants from a case-control study in which the cases met criteria for alcohol dependence. We also examined whether genes of interest were expressed in human brain. AAB was measured using a count of the number of Antisocial Personality Disorder criteria endorsed under criterion A from the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV). Participants were genotyped on the Illumina Human 1M BeadChip. In total, all single-nucleotide polymorphisms (SNPs) accounted for 25% of the variance in AAB, although this estimate was not significant (P=0.09). Enrichment tests indicated that more significantly associated genes were over-represented in seven gene sets, and most were immune related. Our most highly associated SNP (rs4728702, P=5.77 Γ 10(-7)) was located in the protein-coding adenosine triphosphate-binding cassette, sub-family B (MDR/TAP), member 1 (ABCB1). In a gene-based test, ABCB1 was genome-wide significant (q=0.03). Expression analyses indicated that ABCB1 was robustly expressed in the brain. ABCB1 has been implicated in substance use, and in post hoc tests we found that variation in ABCB1 was associated with DSM-IV alcohol and cocaine dependence criterion counts. These results suggest that ABCB1 may confer risk across externalizing behaviors, and are consistent with previous suggestions that immune pathways are associated with externalizing behaviors. The results should be tempered by the fact that we did not replicate the associations for ABCB1 or the gene sets in a less-affected independent sample.
Association results from the genome-wide association study of adult antisocial behavior. On the x axis are single-nucleotide polymorphism (SNP) positions for chromosomes 1β22. On the y axis are negative logarithms (base 10) of the P-values for each SNP, whereby higher values indicate smaller P-values.
(a) Association results from the genome-wide association study (GWAS) of adult antisocial behavior (AAB) for a 200-kb region surrounding rs4728702 in ABCB1 on chromosome 7. (b) Association results from the GWAS of AAB for a 200-kb region surrounding rs28368138 on chromosome 9p. Four genes for type I interferon (IFNA7, IFNA10, IFNA16 and IFNA17) depicted here reached nominal significance (P-value threshold of less than 1 Γ 10β4) in gene-based tests. (c) Association results from the GWAS of AAB for a 200-kb region surrounding rs10985923 on chromosome 9q. Five genes (STRBP, MIR600, RABGAP1, MIR600HG and ZBTB26) depicted here reached nominal significance (P-value threshold of less than 1 Γ 10β4) in gene-based tests. All plots were constructed using LocusZoom.35 Shown on the x axis of all figures are position numbers, and on the y axis are the negative logarithms (base 10) of the P-values for each single-nucleotide polymorphism (SNP), whereby higher values indicate smaller P-values, and local estimates of recombination rates. SNPs are color coded to visualize the haplotype structure in this region, with orange and red coloring indicating SNPs higher in linkage disequilibrium (LD) and blue and green indicating SNPs lower in LD.
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| Genome-Wide Association Studies of a Broad Spectrum of Antisocial Behavior. | 2017 | 28979981 |
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