Historically, molecular genetic research on AAB has been limited to the examination of a small number of candidate genes with purported biological relevance; only recently have researchers begun to conduct atheoretical genome-wide scans for this phenotype.13,15,16 In our genome-wide investigation, we found that autosomal SNPs accounted for ~ 25% of the variation in a dimensional measure of AAB. Although this estimate was not statistically significant , which is likely attributable to our modest sample size, it maps nicely to meta-analytic findings that additive genetic influences account for 32% of the variation in antisocial behavior.Our finding also maps to recent GCTA analyses in a community-based sample, where it was found that common genetic variation accounted for 26% of the variation in a behavioral disinhibition phenotype.16 No SNP reached genome-wide significance in our GWAS of AAB. Our most associated SNP, rs4728702, was located in ABCB1 on chromosome. In our gene-based tests, ABCB1 was significant at the genome-wide level; however, we did not find an association for this gene in our replication sample. In expression analyses, we also found that ABCB1 is robustly expressed in human brain. This provides some biologically plausible evidence that ABCB1 variation could be associated with behavioral outcomes. ABCB1 codes for a member of the adenosine triphosphate-binding cassette transporters, ABCB1 or P-glycoprotein, which transportmolecules across cellular membranes and also across the blood– brain barrier. ABCB1 is considered a pharmacogenetic candidate gene in view of ABCB1 transporters’ ability to change drug pharmacokinetics. Variation in ABCB1 has been previously associated with a number of psychiatric phenotypes, cannabis growing equipment including opioid and cannabis dependence, as well as with treatment outcomes for depression and addiction.
The related rodent gene, Abcb1a, is differentially expressed in three brain regions of alcohol preferring animals compared with non-preferring animals.Furthermore, ethanol exposure changes ABCB1 expression. An in vitro study of human intestinal cells found that ethanol exposure increased messenger RNA ABCB1 expression level, and that these increases were maintained even after a week of ethanol withdrawal.Similarly, ABCB1 expression was increased in lymphoblastoid cell lines following ethanol exposure, and in rodents, Abcb1a expression was increased in the nucleus accumbens of alcohol-preferring rats following alcohol exposure.Taken as a whole, this pattern suggests that ABCB1 has pleiotropic effects across a number of externalizing spectrum behaviors/disorders, and that its expression is affected by ethanol exposure. The former is consistent with findings from the twin and molecular genetics literature, demonstrating that common externalizing disorders and behaviors share genetic influences,and that this shared genetic factor is highly heritable .Supplementary analyses in our own sample were consistent with this hypothesis, and we found evidence that ABCB1 variation was associated with alcohol and cocaine dependence criterion counts. However, we did not find associations between ABCB1 and marijuana or opioid dependence criterion counts. We also found evidence for enrichment across multiple canonical pathways and gene ontologies including cytokine activity, Jak-STAT signaling pathway, toll-like receptor signaling pathway, antigen processing and presentation, cytokine receptor binding and natural killer cell-mediated cytotoxicity. Although the immediate biological relevance of these categories to AAB is not clear, these enrichment findings include many immune-related pathways and may be best interpreted in light of the associations among AAB and alcohol, cannabis, cocaine and opioid dependence criterion counts in the sample.
Immune and inflammatory pathways have been hypothesized to be associated with psychiatric disorders across the internalizing and externalizing spectra.For example, it is known that alcohol alters cytokine activity,induces changes in neuroimmune signaling in the brain48 and that alcohol dependence is associated with low-grade systemic inflammation.49 Likewise, the monocytes of individuals who are cocaine dependent show decreased expression of tumor necrosis factor-α and interleukin-6 proinflammatory cytokines in response to a bacterial ligand relative to controls.Four of the top genes to emerge in our analysis are genes for type I interferon , which reside in a cluster on chromosome 9p. Previous studies demonstrate that interferon A treatment of hepatitis C patients can induce multiple psychiatric symptoms including depression and impulsivity.Although we did not find significant enrichment for these pathways in our replication sample, these results add preliminary evidence to a growing literature that variation in genes in immune-relevant pathways may predispose individuals to AAB and closely related behaviors. The present study expands upon the initial AAB GWAS by Tielbeek et al.as well as more recently published GWAS of a behavioral disinhibition phenotype in two important ways. First, we used a case–control sample where the cases met criteria for alcohol dependence. By virtue of the association between alcohol dependence and AAB, and the relatively high rates of individuals meeting clinical cutoffs for criterion A for ASPD in the present sample compared with American population-based prevalence estimates, it is likely that the sample was enriched for genetic variants predisposing individuals toward externalizing spectrum behaviors such as AAB.
Previous work indicates that the genetic influences on AAB completely overlap with the genetic influences on alcohol dependence, other drug abuse/dependence and conduct disorder—that is, AAB does not have unique genetic influences above and beyond those shared with these other externalizing disorders.In view of this, gene identification efforts for AAB are likely to be more successful in more severely affected samples or in samples where participants high in AAB also tend to have comorbid alcohol or substance-use disorders, such as the COGA sample. In contrast, for example, only 6% of the participants in the Tielbeek et al.community-based sample met their nondiagnostic AAB case criteria. This sample may also have had low rates of comorbid alcohol and other drug diagnoses, limiting the ability to find genome-wide significant effects. Second, we used a dimensional measure of AAB, which is more powerful than a binary diagnostic variable, and better represents the underlying dimensional structure of AAB.These differences may explain, in part, why we were able to detect a significant genetic association in the present sample. Our study should be interpreted in the context of several limitations. First, our sample size was relatively small. Second, because the COGA case–control alcohol dependence sample is highly affected by AAB, the findings emerging from our study may not generalize to lower-risk populations or other types of high-risk populations. Our null replication attempt may be attributable, in part, to the replication sample being relatively less affected than the discovery sample. There are other instances where genetic associations for externalizing behaviors have replicated within highly affected samples, but not less-affected samples. For example, GABRA2 is associated with alcohol dependence in samples where alcohol-dependent cases came from clinically recruited samples and families densely affected by alcoholism,but not community-based samples.A sample recruited for this purpose is likely to be enriched for genetic variation that predisposes individuals to a range of externalizing behavior problems, including AAB;however,cannabis drying trays whether our findings generalize to other populations at high risk for AAB is unknown. Third, because we limited the current analyses to European-Americans, our results may not generalize to other racial and ethnic groups. Fourth, similar to all psychiatric outcomes, antisocial behavior has a developmental component, and evidence from the twin literature suggests that there are genetic influences on adolescent and adult antisocial behavior that are distinct from genetic influences on child antisocial behavior.The degree to which the genetic associations documented here for AAB are also associated with child or adolescent antisocial behavior is not clear. The results from this study provide an empirical starting point for subsequent developmental analyses to examine these questions. Fifth, there are likely to be aspects of the environment that moderate genetic influences on AAB that we did not explicitly examine here but that may be valuable to pursue in subsequent studies. Finally, our genome-wide association approach examined only common genetic variation. There is suggestive evidence that rare nonsynonymous exonic SNPs account for 14% of the variance in a behavioral disinhibition phenotype.
As rare variant-genotyping arrays and whole-genome sequencing become more widely available and cost effective, our understanding of the genetics of AAB will improve. In summary, our goal in this study was to take an atheoretical approach to investigate the molecular genetic basis of AAB in a high-risk sample. The heritability of AAB was 25%, although this estimate did not differ significantly from zero. No SNP reached strict genome-wide significance, but gene-based tests identified an association between ABCB1 and AAB. Expression analyses further indicated that ABCB1 is robustly expressed in the brain, providing some evidence that variation in this gene could be related to a behavioral outcome. Previously documented associations between variants in ABCB1 and other drugs of abuse suggest that ABCB1 may confer general risk across a range of externalizing behaviors, rather than risk that is unique to AAB. This was consistent with post hoc analyses in our sample, where we found that variation in ABCB1 was associated with DSM-IV alcohol and cocaine dependence criteria. We also found enrichment of several immune-related canonical pathways and gene ontologies, which is consistent with previous suggestions that immune and inflammatory pathways are associated with externalizing spectrum behaviors. As a whole, our study goes beyond the candidate gene approach typically taken in studies of AAB, and implicates a gene and gene sets for which there is convergent evidence from other lines of research. These findings, although novel and promising, would benefit from direct replication.More than 500,000 individuals in the United States are homeless at any time and approximately 3 million experience homelessness over the course of a year.The medianage of adults experiencing homelessness has risen and is now approximately 50 years.Homelessness is a risk factor for many adverse health conditions, including aging-related conditions.Individuals experiencing homelessness have an earlier onset of age related problems than the general population. In their 50s and 60s, they have a similar prevalence of geriatric conditions as housed adults in their 70s and 80s.Due to high prevalence of functional and cognitive impairments, researchers and practitioners consider homeless adults “older” at age 50.Pain is a common and challenging symptom, and the risk factors, severity, and duration of pain are well studied in the general population.Chronic non-cancer pain, defined as pain lasting for longer than 3 months not attributable to malignancy, is common.While studies have examined chronic pain among older adults or homeless individuals, little is known about the risk factors for chronic pain in older adults experiencing homelessness.Compared with the general population, people who experience homelessness are more likely to report conditions associated with an increased prevalence and severity of chronic pain, including chronic physical and mental health disorders, substance use disorders, tobacco dependence, and histories of childhood physical or sexual abuse.In addition, people who are homeless experience challenging physical environments which may worsen pain. Improving our understanding of chronic pain in older adults experiencing homelessness may aid efforts to identify effective ways to treat and relieve their suffering. In this study, we describe the severity and duration of pain and its association with demographic and clinical characteristics in a community-recruited sample of homeless adults aged 50 and older. We hypothesized a high prevalence of chronic moderate to severe pain. We explored factors associated with chronic pain, including: gender, race, age, physical environment, history of abuse, substance use, mental health problems, and physical health. During July 2013 to June 2014, we enrolled a population-based sample of 350 homeless adults from overnight shelters, homeless encampments, meal programs, and a recycling center in Oakland, California.Based on the estimates of the number of unique individuals who used each site annually, we approached potential participants in a random order and assessed for interest and preliminary eligibility. Following an eligibility interview, study staff recruited individuals meeting the following criteria: homeless as defined by the Homeless Emergency Assistance and Rapid Transition to Housing Act, English-speaking, aged 50 or over, and able to provide informed consent as verified by using a teach-back mechanism.The HEARTH Act includes both individuals who lack a fixed residence or reside in a place not typically used for sleeping and individuals who are at imminent risk of losing housing within fourteen days. It acknowledges that people who are homeless reside in a variety of environments.We conducted study interviews at a community-based center that provided social services for low-income older adults. Participants did not have to be eligible for, or receive services at the Center. Trained study staff members administered the questionnaires. Participants received gift cards valued at $5and $20 for the eligibility and baseline interviews, respectively. The Institutional Review Board of the University of California, San Francisco approved the study.