Polymorphisms in the A118G SNP of the OPRM1 gene produce different experiences of opioids: A human laboratory phenotype-genotype assessment.

Allelic variations in the A118G SNP of the OPRM1 gene change opioid signaling; however, evaluations of how allelic differences may influence opioid effects are lacking. This human laboratory paradigm examined whether the AA versus AG/GG genotypes determined opioid response profiles. Individuals with limited opioid exposure (N = 100) completed a five-day within-subject, double-blind, placebo-controlled, residential study. Participants were admitted (Day 1), received 4 mg hydromorphone (Day 2) and 0 mg, 2 mg and 8 mg hydromorphone in randomized order (Days 3-5) and completed self-reported visual analog scale (VAS) ratings and Likert scales, observed VAS, and physiological responses at baseline and for 6.5 h post-dose. Outcomes were analysed as peak/nadir effects over time as a function of genotype (available for N = 96 individuals; AG/GG = 13.5%, AA = 86.4%). Participants with AG/GG rated low and moderate doses of hydromorphone as significantly more positive (e.g., Good Effects VAS, coasting, drive, friendly, talkative, stimulation) with fewer negative effects (e.g., itchy skin, nausea, sleepiness), and were also observed as being more talkative and energetic relative to persons with AA. Persons with AG/GG were less physiologically reactive as determined by diastolic blood pressure and heart rate, but had more changes in core temperature compared with those with AA. Persons with AA also demonstrated more prototypic agonist effects across doses; persons with AG/GG showed limited response to 2 mg and 4 mg. Data suggest persons with AG/GG genotype experienced more pleasant and fewer unpleasant responses to hydromorphone relative to persons with AA. Future studies should replicate these laboratory findings in clinical populations to support a precision medicine approach to opioid prescribing.

Sleep Duration Polygenic Risk and Phenotype: Associations with Biomarkers of Accelerated Aging in the Baltimore Longitudinal Study of Aging.

We sought to explore whether genetic risk for, and self-reported, short sleep are associated with biological aging and whether age and sex moderate these associations. Participants were a subset of individuals from the Baltimore Longitudinal Study of Aging who had complete data on self-reported sleep (n = 567) or genotype (n = 367). Outcomes included: Intrinsic Horvath age, Hannum age, PhenoAge, GrimAge, and DNAm-based estimates of plasminogen activator inhibitor-1 (PAI-1) and granulocyte count. Results demonstrated that polygenic risk for short sleep was positively associated with granulocyte count; compared to those reporting <6 hr sleep, those reporting >7 hr demonstrated faster PhenoAge and GrimAge acceleration and higher estimated PAI-1. Polygenic risk for short sleep and self-reported sleep duration interacted with age and sex in their associations with some of the outcomes. Findings highlight that polygenic risk for short sleep and self-reported long sleep is associated with variation in the epigenetic landscape and subsequently aging.

Shared Genetic Etiology between Cortical Brain Morphology and Tobacco, Alcohol, and Cannabis Use.

Genome-wide association studies (GWAS) have identified genetic variants associated with brain morphology and substance use behaviors (SUB). However, the genetic overlap between brain structure and SUB has not been well characterized. We leveraged GWAS summary data of 71 brain imaging measures and alcohol, tobacco, and cannabis use to investigate their genetic overlap using linkage disequilibrium score regression. We used genomic structural equation modeling to model a "common SUB genetic factor" and investigated its genetic overlap with brain structure. Furthermore, we estimated SUB polygenic risk scores (PRS) and examined whether they predicted brain imaging traits using the Adolescent Behavior and Cognitive Development (ABCD) study. We identified 8 significant negative genetic correlations, including between (1) alcoholic drinks per week and average cortical thickness, and (2) intracranial volume with age of smoking initiation. We observed 5 positive genetic correlations, including those between (1) insula surface area and lifetime cannabis use, and (2) the common SUB genetic factor and pericalcarine surface area. SUB PRS were associated with brain structure variation in ABCD. Our findings highlight a shared genetic etiology between cortical brain morphology and SUB and suggest that genetic variants associated with SUB may be causally related to brain structure differences.

Systematic Review and Meta-analysis of the Relationship Between Exposure to Parental Substance Use and Attention-Deficit/Hyperactivity Disorder in Children.

Attention-deficit/hyperactivity disorder (ADHD) is characterized by persistent patterns of inattention, hyperactivity, and impulsiveness. Among US children and adolescents aged 3-17 years, 9.4% have a diagnosis of ADHD. Previous research suggests possible links between parental substance use and ADHD among children. We conducted a systematic review and meta-analysis of 86 longitudinal or retrospective studies of prenatal or postnatal alcohol, tobacco, or other parental substance use and substance use disorders and childhood ADHD and its related behavioral dimensions of inattention and hyperactivity-impulsivity. Meta-analyses were grouped by drug class and pre- and postnatal periods with combined sample sizes ranging from 789 to 135,732. Prenatal exposure to alcohol or tobacco and parent substance use disorders were consistently and significantly associated with ADHD among children. Other parental drug use exposures resulted in inconsistent or non-significant findings. Prevention and treatment of parental substance use may have potential for impacts on childhood ADHD.

Association of common infections with cognitive performance in the Baltimore Epidemiologic Catchment Area study follow-up.

INTRODUCTION: Growing evidence suggests that some common infections are causally associated with cognitive impairment; however, less is known about the burden of multiple infections. METHODS: We investigated the cross-sectional association of positive antibody tests for herpes simplex virus, cytomegalovirus (CMV), Epstein-Barr virus (EBV), varicella zoster virus (VZV), and Toxoplasma gondii (TOX) with Mini-Mental State Examination (MMSE) and delayed verbal recall performance in 575 adults aged 41-97 from the Baltimore Epidemiologic Catchment Area Study. RESULTS: In multivariable-adjusted zero-inflated Poisson (ZIP) regression models, positive antibody tests for CMV (p = .011) and herpes simplex virus (p = .018) were individually associated with poorer MMSE performance (p = .011). A greater number of positive antibody tests among the five tested was associated with worse MMSE performance (p = .001). DISCUSSION: CMV, herpes simplex virus, and the global burden of multiple common infections were independently associated with poorer cognitive performance. Additional research that investigates whether the global burden of infection predicts cognitive decline and Alzheimer's disease biomarker changes is needed to confirm these findings.

Adverse childhood experiences and comorbidity in a cohort of people who have injected drugs.

BACKGROUND: Childhood adversity is associated with the onset of harmful adult substance use and related health problems, but most research on adversity has been conducted in general population samples. This study describes the prevalence of adverse childhood experiences in a cohort of people who have injected drugs and examines the association of these adverse experiences with medical comorbidities in adulthood. METHODS: Six hundred fifty three adults were recruited from a 30-year cohort study on the health of people who have injected drugs living in and around Baltimore, Maryland (Median age = 47.5, Interquartile Range = 42.3-52.3 years; 67.3% male, 81.1% Black). Adverse childhood experiences were assessed retrospectively in 2018 via self-report interview. Lifetime medical comorbidities were ascertained via self-report of a provider diagnosis. Multinomial logistic regression with generalized estimating equations was used to examine the association between adversity and comorbid conditions, controlling for potential confounders. RESULTS: Two hundred twelve participants (32.9%) reported 0-1 adverse childhood experiences, 215 (33.3%) reported 2-4, 145 (22.5%) reported 5-9, and 72 (11.1%) reported ≥10. Neighborhood violence was the most commonly reported adversity (48.5%). Individuals with ≥10 adverse childhood experiences had higher odds for reporting ≥3 comorbidities (Adjusted Odds Ratio = 2.9, 95% CI = 1.2 - 6.8, p = .01). CONCLUSIONS: Among people who have injected drugs, adverse childhood experiences were common and associated with increased occurrence of self-reported medical comorbidities. Findings highlight the persistent importance of adversity for physical health even in a population where all members have used drugs and there is a high burden of comorbidity.

Early Childhood Behavioral and Academic Antecedents of Lifetime Opioid Misuse among Urban Youth.

OBJECTIVE: Opioid misuse has become an epidemic in the United States. In the present study, we examine potential malleable early childhood predictors of opioid misuse including whether childhood achievement, aggressive behavior, attention problems, and peer social preference/likability in first grade predicted opioid misuse and whether these relationships differed depending on participant sex. METHOD: Data are drawn from three cohorts of participants (N = 1,585; 46.7% male) recruited in first grade as part of a series of elementary school-based, universal preventive interventions conducted in a Mid-Atlantic region of the US. In first grade, participants completed standardized achievement tests, teachers reported on attention problems, and peers nominated their classmates with respect to their aggressive behavior and social preference/likability. At approximately age 20, participants reported on their misuse of opioids defined as lifetime use of heroin or misuse of prescription opioids. RESULTS: Higher levels of peer nominations for aggressive behavior in first grade predicted a greater likelihood of opioid misuse. An interaction between participant sex and attention problems was observed such that females higher in attention problems were more likely to misuse opioids, particularly prescription opioids, than females lower in attention problems. An interaction was also found between participant sex and peer likability such that males lower in peer-nominated likability were more likely to misuse opioids relative to males higher in likability. CONCLUSION: Given the malleable nature of attention problems, aggression, and social skills in early childhood, prevention programs that target these behaviors during this developmental period may attenuate risk for opioid misuse.

Developmental effects of maternal smoking during pregnancy on the human frontal cortex transcriptome.

Cigarette smoking during pregnancy is a major public health concern. While there are well-described consequences in early child development, there is very little known about the effects of maternal smoking on human cortical biology during prenatal life. We therefore performed a genome-wide differential gene expression analysis using RNA sequencing (RNA-seq) on prenatal (N = 33; 16 smoking-exposed) as well as adult (N = 207; 57 active smokers) human postmortem prefrontal cortices. Smoking exposure during the prenatal period was directly associated with differential expression of 14 genes; in contrast, during adulthood, despite a much larger sample size, only two genes showed significant differential expression (FDR < 10%). Moreover, 1,315 genes showed significantly different exposure effects between maternal smoking during pregnancy and direct exposure in adulthood (FDR < 10%)-these differences were largely driven by prenatal differences that were enriched for pathways previously implicated in addiction and synaptic function. Furthermore, prenatal and age-dependent differentially expressed genes were enriched for genes implicated in non-syndromic autism spectrum disorder (ASD) and were differentially expressed as a set between patients with ASD and controls in postmortem cortical regions. These results underscore the enhanced sensitivity to the biological effect of smoking exposure in the developing brain and offer insight into how maternal smoking during pregnancy affects gene expression in the prenatal human cortex. They also begin to address the relationship between in utero exposure to smoking and the heightened risks for the subsequent development of neuropsychiatric disorders.

Alcohol trajectories and subsequent risk for opioid misuse in a cohort of urban adolescents.

Background: The opioid epidemic is a public health emergency in the US. Alcohol is the most widely used addictive substance among all age groups; however, the contribution of different alcohol use trajectories throughout adolescence and young adulthood to the development of opioid misuse in young adulthood among urban minority youth has not been investigated. Methods: Data are from a study of 580 youth (85% African American, 67% low SES) residing in Baltimore City followed from ages 6-26. Alcohol trajectories were identified between ages 14 and 26 using group-based trajectory modeling. Opioid misuse was defined as using opioid painkillers without a prescription or using heroin between ages 19 and 26. Opioid misuse outcomes were also investigated separately. Logistic regression examined associations of alcohol trajectories with opioid misuse in young adulthood adjusting for socio-demographics, early use of tobacco and cannabis, neighborhood, and peer factors. Results: Six alcohol use trajectories were identified: Young adult increasing (21.4%), adult increasing (19.1%), abstaining (19.1%), experimenting (15.3%), adolescent increasing (14.8%), and adolescent limited (10.2%). In models fully adjusted for covariates, relative to the abstaining trajectory, the adolescent increasing trajectory was associated with an elevated risk of opioid misuse (aOR = 3.3, 95%CI = 1.4, 7.8) and prescription opioid misuse (aOR = 3.9, 95%CI = 1.4, 10.8) in young adulthood. Conclusions: Escalating alcohol use in adolescence and young adulthood is associated with an elevated risk of opioid misuse in young adulthood in a cohort of predominantly African American and socio-economically disadvantaged young people. Tailored interventions should target high levels of alcohol use during these developmental periods to reduce risk for opioid misuse among disadvantaged youth.

Genetic propensity for risky behavior and depression and risk of lifetime suicide attempt among urban African Americans in adolescence and young adulthood.

Suicide attempts (SA) among African Americans have increased at a greater rate than any other racial/ethnic group. Research in European ancestry populations has indicated that SA are genetically influenced; however, less is known about the genetic contributors that underpin SA among African Americans. We examined whether genetic propensity for depression and risky behaviors (assessed via polygenic risk scores; PRS) independently and jointly are associated with SA among urban, African Americans and whether sex differences exist in these relations. Participants (N = 1,157, 45.0% male) were originally recruited as part of two first grade universal school-based prevention trials. Participants reported in adolescence and young adulthood on whether they ever attempted suicide in their life. Depression and risky behaviors PRS were created based on large-scale genome-wide association studies conducted by Howard et al. (2019) and Karlson Línner et al. (2019), respectively. There was a significant interaction between the risky behavior PRS and depression PRS such that the combination of high risky behavior polygenic risk and low/moderate polygenic risk for depression was associated with greater risk for lifetime SA among the whole sample and African American males specifically. In addition, the risky behavior PRS was significantly positively associated with lifetime SA among African American males. These findings provide preliminary evidence regarding the importance of examining risky behavior and depression polygenic risk in relation to SA among African Americans, though replication of our findings in other African American samples is needed.

Pathways Between a Polygenic Score for Educational Attainment and Higher Educational Attainment in an African American Sample.

We investigated the extent to which performance on standardized achievement tests, executive function (EF), and aggression in childhood and adolescence accounted for the relationship between a polygenic score for educational attainment (EA PGS) and years of education in a community sample of African Americans. Participants (N = 402; 49.9% female) were initially recruited for an elementary school-based prevention trial in a Mid-Atlantic city and followed into adulthood. In first and twelfth grade, participants completed math and reading standardized tests and teachers reported on participants' aggression and EF, specifically impulsivity and concentration problems. At age 20, participants reported on their years of education and post-secondary degrees attained and their genotype was assayed from blood or buccal swabs. An EA PGS was created using results from a large-scale GWAS on EA. A higher EA PGS was associated with higher education indirectly via adolescent achievement. No other mediating mechanisms were significant. Adolescent academic achievement is thus one mechanism through which polygenic propensity for EA influences post-secondary education among urban, African American youth.

Polygenic and environmental influences on the course of African Americans' alcohol use from early adolescence through young adulthood.

The study examined (a) whether alcohol use subgroups could be identified among African Americans assessed from adolescence through early adulthood, and (b) whether subgroup membership was associated with the interaction between internalizing symptoms and antisocial behavior polygenic risk scores (PRSs) and environmental characteristics (i.e., parental monitoring, community disadvantage). Participants (N = 436) were initially recruited for an elementary school-based prevention trial in a Mid-Atlantic city. Youths reported on the frequency of their past year alcohol use from ages 14-26. DNA was obtained from participants at age 21. Internalizing symptoms and antisocial behavior PRSs were created based on a genome-wide association study (GWAS) conducted by Benke et al. (2014) and Tielbeek et al. (2017), respectively. Parental monitoring and community disadvantage were assessed at age 12. Four classes of past year alcohol use were identified: (a) early-onset, increasing; (b) late-onset, moderate use; (c) low steady; and (d) early-onset, decreasing. In high community disadvantaged settings, participants with a higher internalizing symptoms PRS were more likely to be in the early-onset, decreasing class than the low steady class. When exposed to elevated community disadvantage, participants with a higher antisocial behavior PRS were more likely to be in the early-onset, increasing class than the early-onset, decreasing and late-onset, moderate use classes.

Social Competence in Parents Increases Children's Educational Attainment: Replicable Genetically-Mediated Effects of Parenting Revealed by Non-Transmitted DNA.

We recently reported an association of offspring educational attainment with polygenic risk scores (PRS) computed on parent's non-transmitted alleles for educational attainment using the second GWAS meta-analysis article on educational attainment published by the Social Science Genetic Association Consortium. Here we test the replication of these findings using a more powerful PRS from the third GWAS meta-analysis article by the Consortium. Each of the key findings of our previous paper is replicated using this improved PRS (N = 2335 adolescent twins and their genotyped parents). The association of children's attainment with their own PRS increased substantially with the standardized effect size, moving from ß = 0.134, 95% CI = 0.079, 0.188 for EA2, to ß = 0.223, 95% CI = 0.169, 0.278, p < .001, for EA3. Parent's PRS again predicted the socioeconomic status (SES) they provided to their offspring and increased from ß = 0.201, 95% CI = 0.147, 0.256 to ß = 0.286, 95% CI = 0.239, 0.333. Importantly, the PRS for alleles not transmitted to their offspring - therefore acting via the parenting environment - was increased in effect size from ß = 0.058, 95% CI = 0.003, 0.114 to ß = 0.067, 95% CI = 0.012, 0.122, p = .016. As previously found, this non-transmitted genetic effect was fully accounted for by parental SES. The findings reinforce the conclusion that genetic effects of parenting are substantial, explain approximately one-third the magnitude of an individual's own genetic inheritance and are mediated by parental socioeconomic competence.

The Nature of Nurture: Using a Virtual-Parent Design to Test Parenting Effects on Children's Educational Attainment in Genotyped Families.

Research on environmental and genetic pathways to complex traits such as educational attainment (EA) is confounded by uncertainty over whether correlations reflect effects of transmitted parental genes, causal family environments, or some, possibly interactive, mixture of both. Thus, an aggregate of thousands of alleles associated with EA (a polygenic risk score; PRS) may tap parental behaviors and home environments promoting EA in the offspring. New methods for unpicking and determining these causal pathways are required. Here, we utilize the fact that parents pass, at random, 50% of their genome to a given offspring to create independent scores for the transmitted alleles (conventional EA PRS) and a parental score based on alleles not transmitted to the offspring (EA VP_PRS). The formal effect of non-transmitted alleles on offspring attainment was tested in 2,333 genotyped twins for whom high-quality measures of EA, assessed at age 17 years, were available, and whose parents were also genotyped. Four key findings were observed. First, the EA PRS and EA VP_PRS were empirically independent, validating the virtual-parent design. Second, in this family-based design, children's own EA PRS significantly predicted their EA (ß = 0.15), ruling out stratification confounds as a cause of the association of attainment with the EA PRS. Third, parental EA PRS predicted the SES environment parents provided to offspring (ß = 0.20), and parental SES and offspring EA were significantly associated (ß = 0.33). This would suggest that the EA PRS is at least as strongly linked to social competence as it is to EA, leading to higher attained SES in parents and, therefore, a higher experienced SES for children. In a full structural equation model taking account of family genetic relatedness across multiple siblings the non-transmitted allele effects were estimated at similar values; but, in this more complex model, confidence intervals included zero. A test using the forthcoming EA3 PRS may clarify this outcome. The virtual-parent method may be applied to clarify causality in other phenotypes where observational evidence suggests parenting may moderate expression of other outcomes, for instance in psychiatry.

Critical Issues in the Inclusion of Genetic and Epigenetic Information in Prevention and Intervention Trials.

Human genetic research in the past decade has generated a wealth of data from the genome-wide association scan era, much of which is catalogued and freely available. These data will typically test the relationship between a single nucleotide variant or polymorphism (SNP) and some outcome, disease, or trait. Ongoing investigations will yield a similar wealth of data regarding epigenetic phenomena. These data will typically test the relationship between DNA methylation at a single genomic location/region and some outcome. Most of these findings will be the result of cross-sectional investigations typically using ascertained cases and controls. Consequently, most methodological consideration focuses on methods appropriate for simple case-control comparisons. It is expected that a growing number of investigators with longitudinal experimental prevention or intervention cohorts will also measure genetic and epigenetic indicators as part of their investigations, harvesting the wealth of information generated by the genome-wide association study (GWAS) era to allow for targeted hypothesis testing in the next generation of prevention and intervention trials. Herein, we discuss appropriate quality control and statistical modelling of genetic, polygenic, and epigenetic measures in longitudinal models. We specifically discuss quality control, population stratification, genotype imputation, pathway approaches, and proper modelling of an interaction between a specific genetic variant and an environment variable (GxE interaction).

Informing Prevention and Intervention Policy Using Genetic Studies of Resistance.

The common paradigm for conceptualizing the influence of genetic and environmental factors on a particular disease relies on the concept of risk. Consequently, the bulk of etiologic, including genetic, work focuses on "risk" factors. These factors are aggregated at the high end of the distribution of liability to disease, the latent variable underlying the distribution of probability and severity of a disorder. However, liability has a symmetric but distinct aspect to risk, resistance to disorder. Resistance factors, aggregated at the low end of the liability distribution and supporting health and recovery, appear to be more promising for effective prevention and intervention. Herein, we discuss existing work on resistance factors, highlighting those with known genetic influences. We examine the utility of incorporating resistance genetics in prevention and intervention trials and compare the statistical power of a series of ascertainment schemes to develop a general framework for examining resistance outcomes in genetically informative designs. We find that an approach that samples individuals discordant on measured liability, a low-risk design, is the most feasible design and yields power equivalent to or higher than commonly used designs for detecting resistance genetic and environmental effects.

Variants on chromosome 4q21 near PKD2 and SIBLINGs are associated with dental caries.

A recent genome-wide association study (GWAS) for dental caries nominated the chromosomal region 4q21 near ABCG2, PKD2 and the SIBLING (small integrin-binding ligand N-linked glycoprotein) gene family. In this investigation, we followed up and fine-mapped this region using a tag-SNP (single-nucleotide polymorphism) approach in 13 age- and race-stratified samples from 6 independent studies (N=4089). Participants were assessed for dental caries via intraoral examination and 49 tag-SNPs were genotyped capturing much of the variation in the 4q21 locus. Linear models were used to test for genetic association, while adjusting for sex, age and components of ancestry. SNPs in and near PKD2 showed significant evidence of association in individual samples of black adults (rs17013735, P-value=0.0009) and white adults (rs11938025; P-value=0.0005; rs2725270, P-value=0.003). Meta-analyses across black adult samples recapitulated the association with rs17013735 (P-value=0.003), which occurs at low frequency in non-African populations, possibly explaining the race specificity of the effect. In addition to race-specific associations, we also observed evidence of gene-by-fluoride exposure interaction effects in white adults for SNP rs2725233 upstream of PKD2 (P=0.002). Our results show evidence of regional replication, though no single variant clearly accounted for the original GWAS signal. Therefore, while we interpret our results as strengthening the hypothesis that chromosome 4q21 may impact dental caries, additional work is needed.

Genomewide Association Study of Alcohol Dependence Identifies Risk Loci Altering Ethanol-Response Behaviors in Model Organisms.

BACKGROUND: Alcohol dependence (AD) shows evidence for genetic liability, but genes influencing risk remain largely unidentified. METHODS: We conducted a genomewide association study in 706 related AD cases and 1,748 unscreened population controls from Ireland. We sought replication in 15,496 samples of European descent. We used model organisms (MOs) to assess the role of orthologous genes in ethanol (EtOH)-response behaviors. We tested 1 primate-specific gene for expression differences in case/control postmortem brain tissue. RESULTS: We detected significant association in COL6A3 and suggestive association in 2 previously implicated loci, KLF12 and RYR3. None of these signals are significant in replication. A suggestive signal in the long noncoding RNA LOC339975 is significant in case:control meta-analysis, but not in a population sample. Knockdown of a COL6A3 ortholog in Caenorhabditis elegans reduced EtOH sensitivity. Col6a3 expression correlated with handling-induced convulsions in mice. Loss of function of the KLF12 ortholog in C. elegans impaired development of acute functional tolerance (AFT). Klf12 expression correlated with locomotor activation following EtOH injection in mice. Loss of function of the RYR3 ortholog reduced EtOH sensitivity in C. elegans and rapid tolerance in Drosophila. The ryanodine receptor antagonist dantrolene reduced motivation to self-administer EtOH in rats. Expression of LOC339975 does not differ between cases and controls but is reduced in carriers of the associated rs11726136 allele in nucleus accumbens (NAc). CONCLUSIONS: We detect association between AD and COL6A3, KLF12, RYR3, and LOC339975. Despite nonreplication of COL6A3, KLF12, and RYR3 signals, orthologs of these genes influence behavioral response to EtOH in MOs, suggesting potential involvement in human EtOH response and AD liability. The associated LOC339975 allele may influence gene expression in human NAc. Although the functions of long noncoding RNAs are poorly understood, there is mounting evidence implicating these genes in multiple brain functions and disorders.

An inherited duplication at the gene p21 Protein-Activated Kinase 7 (PAK7) is a risk factor for psychosis.

Identifying rare, highly penetrant risk mutations may be an important step in dissecting the molecular etiology of schizophrenia. We conducted a gene-based analysis of large (>100 kb), rare copy-number variants (CNVs) in the Wellcome Trust Case Control Consortium 2 (WTCCC2) schizophrenia sample of 1564 cases and 1748 controls all from Ireland, and further extended the analysis to include an additional 5196 UK controls. We found association with duplications at chr20p12.2 (P = 0.007) and evidence of replication in large independent European schizophrenia (P = 0.052) and UK bipolar disorder case-control cohorts (P = 0.047). A combined analysis of Irish/UK subjects including additional psychosis cases (schizophrenia and bipolar disorder) identified 22 carriers in 11 707 cases and 10 carriers in 21 204 controls [meta-analysis Cochran-Mantel-Haenszel P-value = 2 × 10(-4); odds ratio (OR) = 11.3, 95% CI = 3.7, ∞]. Nineteen of the 22 cases and 8 of the 10 controls carried duplications starting at 9.68 Mb with similar breakpoints across samples. By haplotype analysis and sequencing, we identified a tandem ~149 kb duplication overlapping the gene p21 Protein-Activated Kinase 7 (PAK7, also called PAK5) which was in linkage disequilibrium with local haplotypes (P = 2.5 × 10(-21)), indicative of a single ancestral duplication event. We confirmed the breakpoints in 8/8 carriers tested and found co-segregation of the duplication with illness in two additional family members of one of the affected probands. We demonstrate that PAK7 is developmentally co-expressed with another known psychosis risk gene (DISC1) suggesting a potential molecular mechanism involving aberrant synapse development and plasticity.

Association of the OPRM1 Variant rs1799971 (A118G) with Non-Specific Liability to Substance Dependence in a Collaborative de novo Meta-Analysis of European-Ancestry Cohorts.

The mu1 opioid receptor gene, OPRM1, has long been a high-priority candidate for human genetic studies of addiction. Because of its potential functional significance, the non-synonymous variant rs1799971 (A118G, Asn40Asp) in OPRM1 has been extensively studied, yet its role in addiction has remained unclear, with conflicting association findings. To resolve the question of what effect, if any, rs1799971 has on substance dependence risk, we conducted collaborative meta-analyses of 25 datasets with over 28,000 European-ancestry subjects. We investigated non-specific risk for "general" substance dependence, comparing cases dependent on any substance to controls who were non-dependent on all assessed substances. We also examined five specific substance dependence diagnoses: DSM-IV alcohol, opioid, cannabis, and cocaine dependence, and nicotine dependence defined by the proxy of heavy/light smoking (cigarettes-per-day >20 vs. ≤ 10). The G allele showed a modest protective effect on general substance dependence (OR = 0.90, 95% C.I. [0.83-0.97], p value = 0.0095, N = 16,908). We observed similar effects for each individual substance, although these were not statistically significant, likely because of reduced sample sizes. We conclude that rs1799971 contributes to mechanisms of addiction liability that are shared across different addictive substances. This project highlights the benefits of examining addictive behaviors collectively and the power of collaborative data sharing and meta-analyses.