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Although high-dimensional clinical data (HDCD) are increasingly available in biobank-scale datasets, their use for genetic discovery remains challenging. Here we introduce an unsupervised deep learning model, Representation Learning for Genetic Discovery on Low-Dimensional Embeddings (REGLE), for discovering associations between genetic variants and HDCD. REGLE leverages variational autoencoders to compute nonlinear disentangled embeddings of HDCD, which become the inputs to genome-wide association studies (GWAS). REGLE can uncover features not captured by existing expert-defined features and enables the creation of accurate disease-specific polygenic risk scores (PRSs) in datasets with very few labeled data. We apply REGLE to perform GWAS on respiratory and circulatory HDCD—spirograms measuring lung function and photoplethysmograms measuring blood volume changes. REGLE replicates known loci while identifying others not previously detected. REGLE are predictive of overall survival, and PRSs constructed from REGLE loci improve disease prediction across multiple biobanks. Overall, REGLE contain clinically relevant information beyond that captured by existing expert-defined features, leading to improved genetic discovery and disease prediction.

Hypertension (HTN) involves genetic variability in the renin‐angiotensin system and influences antihypertensive response. We previously reported that angiotensinogen (AGT) messenger RNA (mRNA) is endogenously bound by miR‐122‐5p and rs699 A > G decreases reporter mRNA in the microRNA functional‐assay PASSPORT‐seq. The AGTpromoter variant rs5051 C > T is in linkage disequilibrium (LD) with rs699 A > G and increases AGTtranscription. The independent effect of these variants is understudied due to their LD therefore we aimed to test the hypothesis that increased AGTby rs5051 C > T counterbalances AGTdecreased by rs699 A > G, and when these variants occur independently, it translates to HTN‐related phenotypes. We used in silico, in vitro, in vivo, and retrospective models to test this hypothesis. In silico, rs699 A > G is predicted to increase miR‐122‐5p binding affinity by 3%. Mir‐eCLIP results show rs699 is 40–45 nucleotides from the strongest microRNA‐binding site in the AGTmRNA. Unexpectedly, rs699 A > G increases AGTmRNA in an AGT‐plasmid‐cDNA HepG2 expression model. Genotype‐Tissue Expression (GTEx) and UK Biobank analyses demonstrate liver AGTexpression and HTN phenotypes are not different when rs699 A > G occurs independently from rs5051 C > T. However, GTEx and the in vitro experiments suggest rs699 A > G confers cell‐type‐specific effects on AGTmRNA abundance, and suggest paracrine renal renin‐angiotensin‐system perturbations could mediate the rs699 A > G associations with HTN. We found that rs5051 C > T and rs699 A > G significantly associate with systolic blood pressure in Black participants in the UK Biobank, demonstrating a fourfold larger effect than in White participants. Further studies are warranted to determine if altered antihypertensive response in Black individuals might be due to rs5051 C > T or rs699 A > G. Studies like this will help clinicians move beyond the use of race as a surrogate for genotype. This study successfully tests the overarching hypothesis that rs699 A > G reduces angiotensinogen (AGT) expression independently from rs5051 C > T in the liver, demonstrating that these variants instead may be involved in influencing hypertension through nonliver‐mediated mechanisms.The results demonstrate that rs699 A > G and rs5051 C > T are associated with AGTmessenger RNA abundance in a cell‐type‐specific manner and have small but clinically meaningful associations (up to 2.7 mmHg) with blood pressure.The association between rs699 A > G and rs5051 C > T and increased AGTexpression in the kidney may have clinical significance since the kidney expresses the necessary enzymes to convert AGT to the prohypertensive angiotensin II as well as expressing the angiotensin II and pressor‐control receptors responsible for blood pressure‐raising effects.Further studies are warranted to investigate the potential for direct effects of rs699 A > G or rs5051 to the kidney and to determine if the reason for altered antihypertensive response in Black individuals might be due, in part, to the increased allele frequency of rs5051 C > T or rs699 A > G. This study successfully tests the overarching hypothesis that rs699 A > G reduces angiotensinogen (AGT) expression independently from rs5051 C > T in the liver, demonstrating that these variants instead may be involved in influencing hypertension through nonliver‐mediated mechanisms. The results demonstrate that rs699 A > G and rs5051 C > T are associated with AGTmessenger RNA abundance in a cell‐type‐specific manner and have small but clinically meaningful associations (up to 2.7 mmHg) with blood pressure. The association between rs699 A > G and rs5051 C > T and increased AGTexpression in the kidney may have clinical significance since the kidney expresses the necessary enzymes to convert AGT to the prohypertensive angiotensin II as well as expressing the angiotensin II and pressor‐control receptors responsible for blood pressure‐raising effects. Further studies are warranted to investigate the potential for direct effects of rs699 A > G or rs5051 to the kidney and to determine if the reason for altered antihypertensive response in Black individuals might be due, in part, to the increased allele frequency of rs5051 C > T or rs699 A > G.

Despite substantial progress, causal variants are identified only for a minority of familial Parkinson’s disease (PD) cases, leaving high-risk pathogenic variants unidentified1,2. To identify such variants, we uniformly processed exome sequencing data of 2,184 index familial PD cases and 69,775 controls. Exome-wide analyses converged on RAB32as a novel PD gene identifying c.213C > G/p.S71R as a high-risk variant presenting in ~0.7% of familial PD cases while observed in only 0.004% of controls (odds ratio of 65.5). This variant was confirmed in all cases via Sanger sequencing and segregated with PD in three families. RAB32encodes a small GTPase known to interact with LRRK2 (refs. 3,4). Functional analyses showed that RAB32 S71R increases LRRK2 kinase activity, as indicated by increased autophosphorylation of LRRK2 S1292. Here our results implicate mutant RAB32 in a key pathological mechanism in PD—LRRK2 kinase activity5–7—and thus provide novel insights into the mechanistic connections between RAB family biology, LRRK2 and PD risk.

Alcohol use disorder (AUD) is a complex genetic disorder characterized by problems arising from excessive alcohol consumption. Identifying functional genetic variations that contribute to risk for AUD is a major goal. Alternative splicing of RNA mediates the flow of genetic information from DNA to gene expression and expands proteome diversity. We asked whether alternative splicing could be a risk factor for AUD. Herein, we used a Mendelian randomization (MR)-based approach to identify skipped exons (the predominant splicing event in brain) that contribute to AUD risk. Genotypes and RNA-seq data from the CommonMind Consortium were used as the training dataset to develop predictive models linking individual genotypes to exon skipping in the prefrontal cortex. We applied these models to data from the Collaborative Studies on Genetics of Alcoholism to examine the association between the imputed cis-regulated splicing outcome and the AUD-related traits. We identified 27 exon skipping events that were predicted to affect AUD risk; six of these were replicated in the Australian Twin-family Study of Alcohol Use Disorder. Their host genes are DRC1, ELOVL7, LINC00665, NSUN4, SRRM2and TBC1D5. The genes downstream of these splicing events are enriched in neuroimmune pathways. The MR-inferred impacts of the ELOVL7skipped exon on AUD risk was further supported in four additional large-scale genome-wide association studies. Additionally, this exon contributed to changes of gray matter volumes in multiple brain regions, including the visual cortex known to be involved in AUD. In conclusion, this study provides strong evidence that RNA alternative splicing impacts the susceptibility to AUD and adds new information on AUD-relevant genes and pathways. Our framework is also applicable to other types of splicing events and to other complex genetic disorders.

Chronic obstructive pulmonary disease (COPD), the third leading cause of death worldwide, is highly heritable. While COPD is clinically defined by applying thresholds to summary measures of lung function, a quantitative liability score has more power to identify genetic signals. Here we train a deep convolutional neural network on noisy self-reported and International Classification of Diseases labels to predict COPD case–control status from high-dimensional raw spirograms and use the model’s predictions as a liability score. The machine-learning-based (ML-based) liability score accurately discriminates COPD cases and controls, and predicts COPD-related hospitalization without any domain-specific knowledge. Moreover, the ML-based liability score is associated with overall survival and exacerbation events. A genome-wide association study on the ML-based liability score replicates existing COPD and lung function loci and also identifies 67 new loci. Lastly, our method provides a general framework to use ML methods and medical-record-based labels that does not require domain knowledge or expert curation to improve disease prediction and genomic discovery for drug design.

Introduction:Suicidal thoughts and behaviors have partially distinct genetic etiologies. Methods:We used PRS-CS to create polygenic risk scores (PRSs) from GWAS of non-suicidal self-injury, broad-sense self-harm ideation, nonfatal suicide attempt, death by suicide, and depression. Using mixed-effect models, we estimated whether these PRSs were associated with a range of suicidal thoughts and behaviors in the Collaborative Study on the Genetics of Alcoholism (N= 7,526). Results:All PRSs were significantly associated with suicidal ideation and suicide attempt (betas = 0.08–0.44, false discovery rate [FDR] <0.023). All PRSs except non-suicidal self-injury PRS were associated with active suicidal ideation (betas = 0.14–0.22, FDR <0.003). Several associations remained significant in models where all significant PRSs were included as simultaneous predictors, and when all PRSs predicted suicide attempt, the PRS together explained 6.2% of the variance in suicide attempt. Significant associations were also observed between some PRSs and persistent suicidal ideation, non-suicidal self-injury, compounded suicide attempt, and desire to die. Conclusion:Our findings suggest that PRS for depression does not explain the entirety of the variance in suicidal thoughts and behaviors, with PRS specifically for suicidal thoughts and behaviors making additional and sometimes unique contributions.

Recent genome-wide association studies (GWAS) have identified genetic markers of post-traumatic stress disorder (PTSD) in civilian and military populations. However, studies have yet to examine the genetics of PTSD while factoring in risk for alcohol dependence, which commonly co-occur. We examined genome-wide associations for DSM-IV PTSD among 4,978 trauma-exposed participants (31% with alcohol dependence, 50% female, 30% African ancestry) from the Collaborative Study on the Genetics of Alcoholism (COGA). We also examined associations of polygenic risk scores (PRS) derived from the Psychiatric Genomics Consortium (PGC)-PTSD Freeze 2 (N= 3533) and Million Veterans Program GWAS of PTSD (N= 5200) with PTSD and substance dependence in COGA, and moderating effects of sex and alcohol dependence. 7.3% of COGA participants met criteria for PTSD, with higher rates in females (10.1%) and those with alcohol dependence (12.3%). No independent loci met genome-wide significance in the PTSD meta-analysis of European (EA) and African ancestry (AA) participants. The PGC-PTSD PRS was associated with increased risk for PTSD (B= 0.126, p< 0.001), alcohol dependence (B= 0.231, p< 0.001), and cocaine dependence (B= 0.086, p< 0.01) in EA individuals. A significant interaction was observed, such that EA individuals with alcohol dependence and higher polygenic risk for PTSD were more likely to have PTSD (B= 0.090, p< 0.01) than those without alcohol dependence. These results further support the importance of examining substance dependence, specifically alcohol dependence, and PTSD together when investigating genetic influence on these disorders.

Variation in liability to cannabis use disorder has a strong genetic component (estimated twin and family heritability about 50–70%) and is associated with negative outcomes, including increased risk of psychopathology. The aim of the study was to conduct a large genome-wide association study (GWAS) to identify novel genetic variants associated with cannabis use disorder.

Early identification of individuals at high risk for alcohol use disorder (AUD) coupled with prompt interventions could reduce the incidence of AUD. In this study, we investigated whether Polygenic Risk Scores (PRS) can be used to evaluate the risk for AUD and AUD severity (as measured by the number of DSM‐5 AUD diagnostic criteria met) and compared their performance with a measure of family history of AUD. We studied individuals of European ancestry from the Collaborative Study on the Genetics of Alcoholism (COGA). DSM‐5 diagnostic criteria were available for 7203 individuals, of whom 3451 met criteria for DSM‐IV alcohol dependence or DSM‐5 AUD and 1616 were alcohol‐exposed controls aged ≥21 years with no history of AUD or drug dependence. Further, 4842 individuals had a positive first‐degree family history of AUD (FH+), 2722 had an unknown family history (FH?), and 336 had a negative family history (FH−). PRS were derived from a meta‐analysis of a genome‐wide association study of AUD from the Million Veteran Program and scores from the problem subscale of the Alcohol Use Disorders Identification Test in the UK Biobank. We used mixed models to test the association between PRS and risk for AUD and AUD severity. AUD cases had higher PRS than controls with PRS increasing as the number of DSM‐5 diagnostic criteria increased (p‐values ≤ 1.85E−05) in the full COGA sample, the FH+ subsample, and the FH? subsample. Individuals in the top decile of PRS had odds ratios (OR) for developing AUD of 1.96 (95% CI: 1.54 to 2.51, p‐value = 7.57E−08) and 1.86 (95% CI: 1.35 to 2.56, p‐value = 1.32E−04) in the full sample and the FH+ subsample, respectively. These values are comparable to previously reported ORs for a first‐degree family history (1.91 to 2.38) estimated from national surveys. PRS were also significantly associated with the DSM‐5 AUD diagnostic criterion count in the full sample, the FH+ subsample, and the FH? subsample (p‐values ≤6.7E−11). PRS remained significantly associated with AUD and AUD severity after accounting for a family history of AUD (p‐values ≤6.8E−10). Both PRS and family history were associated with AUD and AUD severity, indicating that these risk measures assess distinct aspects of liability to AUD traits. We calculated polygenic risk scores (PRS) using variants having the same directions of effects in discovery datasets to exclude study‐specific findings and findings due to random variations. The PRS were significantly associated with AUD and AUD severity. Those in the top decile of PRS had odds ratios of 1.96 to develop AUD, comparable to odds ratios of the family history of AUD. PRS were also independent of family history and especially useful when family history information is not available.

Rodent paradigms and human genome‐wide association studies (GWAS) on drug use have the potential to provide biological insight into the pathophysiology of addiction. Using GeneWeaver, we created rodent alcohol and nicotine gene‐sets derived from 19 gene expression studies on alcohol and nicotine outcomes. We partitioned the SNP heritability of these gene‐sets using four large human GWAS: (1) alcoholic drinks per week, (2) problematic alcohol use, (3) cigarettes per day, and (4) smoking cessation. We benchmarked our findings with curated human alcohol and nicotine addiction gene‐sets and performed specificity analyses using other rodent gene‐sets (e.g., locomotor behavior) and other human GWAS (e.g., height). The rodent alcohol gene‐set was enriched for heritability of drinks per week, cigarettes per day, and smoking cessation, but not problematic alcohol use. However, the rodent nicotine gene‐set was not significantly associated with any of these traits. Both rodent gene‐sets showed enrichment for several non‐substance‐use GWAS, and the extent of this relationship tended to increase as a function of trait heritability. In general, larger gene‐sets demonstrated more significant enrichment. Finally, when evaluating human traits with similar heritabilities, both rodent gene‐sets showed greater enrichment for substance use traits. Our results suggest that rodent gene expression studies can help to identify genes that contribute to the heritability of some substance use traits in humans, yet there was less specificity than expected. We outline various limitations, interpretations, and considerations for future research. What can rodent brains tell you about your genetic predisposition to drug use? Using a rich array of animal models and huge human genetic datasets on nicotine and alcohol use, we found that rodent paradigms of alcohol use recapitulated the genetic predisposition of human substance use. Specifically, we found that rodent paradigms of binge drinking aligned with the genetic vulnerabilities of alcohol and tobacco consumption.

Aberrant connectivity of large-scale brain networks has been observed among individuals with alcohol use disorders (AUDs) as well as in those at risk, suggesting deficits in neural communication between brain regions in the liability to develop AUD. Electroencephalographical (EEG) coherence, which measures the degree of synchrony between brain regions, may be a useful measure of connectivity patterns in neural networks for studying the genetics of AUD. In 8810 individuals (6644 of European and 2166 of African ancestry) from the Collaborative Study on the Genetics of Alcoholism (COGA), we performed a Multi-Trait Analyses of genome-wide association studies (MTAG) on parietal resting-state theta (3–7 Hz) EEG coherence, which previously have been associated with AUD. We also examined developmental effects of GWAS findings on trajectories of neural connectivity in a longitudinal subsample of 2316 adolescent/young adult offspring from COGA families (ages 12–30) and examined the functional and clinical significance of GWAS variants. Six correlated single nucleotide polymorphisms located in a brain-expressed lincRNA (ENSG00000266213) on chromosome 18q23 were associated with posterior interhemispheric low theta EEG coherence (3–5 Hz). These same variants were also associated with alcohol use behavior and posterior corpus callosum volume, both in a subset of COGA and in the UK Biobank. Analyses in the subsample of COGA offspring indicated that the association of rs12954372 with low theta EEG coherence occurred only in females, most prominently between ages 25 and 30 (p< 2 × 10-9). Converging data provide support for the role of genetic variants on chromosome 18q23 in regulating neural connectivity and alcohol use behavior, potentially via dysregulated myelination. While findings were less robust, genome-wide associations were also observed with rs151174000 and parieto-frontal low theta coherence, rs14429078 and parieto-occipital interhemispheric high theta coherence, and rs116445911 with centro-parietal low theta coherence. These novel genetic findings highlight the utility of the endophenotype approach in enhancing our understanding of mechanisms underlying addiction susceptibility.

Genome-wide association studies (GWAS) of complex traits, such as alcohol use disorders (AUD), usually identify variants in non-coding regions and cannot by themselves distinguish whether the associated variants are functional or in linkage disequilibrium with the functional variants. Transcriptome studies can identify genes whose expression differs between alcoholics and controls. To test which variants associated with AUD may cause expression differences, we integrated data from deep RNA-seq and GWAS of four postmortem brain regions from 30 subjects with AUD and 30 controls to analyze allele-specific expression (ASE). We identified 88 genes with differential ASE in subjects with AUD compared to controls. Next, to test one potential mechanism contributing to the differential ASE, we analyzed single nucleotide polymorphisms (SNPs) in the 3′ untranslated regions (3′UTR) of these genes. Of the 88 genes with differential ASE, 61 genes contained 437 SNPs in the 3′UTR with at least one heterozygote among the subjects studied. Using a modified PASSPORT-seq (parallel assessment of polymorphisms in miRNA target-sites by sequencing) assay, we identified 25 SNPs that affected RNA levels in a consistent manner in two neuroblastoma cell lines, SH-SY5Y and SK-N-BE(2). Many of these SNPs are in binding sites of miRNAs and RNA-binding proteins, indicating that these SNPs are likely causal variants of AUD-associated differential ASE. In sum, we demonstrate that a combination of computational and experimental approaches provides a powerful strategy to uncover functionally relevant variants associated with the risk for AUD.

African Americans (AA) have lower prevalence of alcohol dependence and higher subjective response to alcohol than European Americans. Genome‐wide association studies (GWAS) have identified genes/variants associated with alcohol dependence specifically in AA; however, the sample sizes are still not large enough to detect variants with small effects. Admixture mapping is an alternative way to identify alcohol dependence genes/variants that may be unique to AA. In this study, we performed the first admixture mapping of DSM‐IV alcohol dependence diagnosis, DSM‐IV alcohol dependence criterion count, and two scores from the self‐rating of effects of ethanol (SRE) as measures of response to alcohol: the first five times of using alcohol (SRE‐5) and average of SRE across three times (SRE‐T). Findings revealed a region on chromosome 4 that was genome‐wide significant for SRE‐5 (pvalue = 4.18E‐05). Fine mapping did not identify a single causal variant to be associated with SRE‐5; instead, conditional analysis concluded that multiple variants collectively explained the admixture mapping signal. PPARGC1A, a gene that has been linked to alcohol consumption in previous studies, is located in this region. Our finding suggests that admixture mapping is a useful tool to identify genes/variants that may have been missed by current GWAS approaches in admixed populations.

Genome‐wide association studies (GWAS) of alcohol dependence (AD) and related phenotypes have identified multiple loci, but the functional variants underlying the loci have in most cases not been identified. Noncoding variants can influence phenotype by affecting gene expression; for example, variants in the 3′ untranslated regions (3′UTR) can affect gene expression posttranscriptionally. We adapted a high‐throughput assay known as PASSPORT‐seq (parallel assessment of polymorphisms in miRNA target sites by sequencing) to identify among variants associated with AD and related phenotypes those that cause differential expression in neuronal cell lines. Based upon meta‐analyses of alcohol‐related traits in African American and European Americans in the Collaborative Study on the Genetics of Alcoholism, we tested 296 single nucleotide polymorphisms (SNPs with meta‐analysis pvalues ≤ 0.001) that were located in 3′UTRs. We identified 60 SNPs that affected gene expression (false discovery rate [FDR] < 0.05) in SH‐SY5Y cells and 92 that affected expression in SK‐N‐BE(2) cells. Among these, 30 SNPs altered RNA levels in the same direction in both cell lines. Many of these SNPs reside in the binding sites of miRNAs and RNA‐binding proteins and are expression quantitative trait loci of genes including KIF6,FRMD4A,CADM2,ADD2,PLK2, and GAS7. The SNPs identified in the PASSPORT‐seq assay are functional variants that might affect the risk for AD and related phenotypes. Our study provides insights into gene regulation in AD and demonstrates the value of PASSPORT‐seq as a tool to screen genetic variants in GWAS loci for one potential mechanism of action. Using a high‐throughput assay (PASSPORT‐seq) to test SNPs within loci affecting risk for alcohol dependence, we identified SNPs in 3’ untranslated regions that cause differential allele expression in neuronal cell lines: 60 in SH‐SY5Y cells and 92 in SK‐N‐BE(2) cells; 30 of these altered RNA levels in the same direction in both. Many reside in binding sites of miRNAs and RNA‐binding proteins and are expression quantitative trait loci for genes including KIF6, FRMD4A, CADM2, ADD2, PLK2, and GAS7.

Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P< 5 × 10−8in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P< 5 × 10−8) in the discovery samples. Ten novel SNVs, including rs12616219 near TMEM182, were followed-up and five of them (rs462779 in REV3L, rs12780116 in CNNM2, rs1190736 in GPR101, rs11539157 in PJA1, and rs12616219 near TMEM182) replicated at a Bonferroni significance threshold (P< 4.5 × 10−3) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, in CCDC141and two low-frequency SNVs in CEP350and HDGFRP2. Functional follow-up implied that decreased expression of REV3Lmay lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation.

To provide insights into the biology of opioid dependence (OD) and opioid use (i.e., exposure, OE), we completed a genome-wide analysis comparing 4503 OD cases, 4173 opioid-exposed controls, and 32,500 opioid-unexposed controls, including participants of European and African descent (EUR and AFR, respectively). Among the variants identified, rs9291211 was associated with OE (exposed vs. unexposed controls; EUR z= −5.39, p= 7.2 × 10–8). This variant regulates the transcriptomic profiles of SLC30A9and BEND4in multiple brain tissues and was previously associated with depression, alcohol consumption, and neuroticism. A phenome-wide scan of rs9291211 in the UK Biobank (N> 360,000) found association of this variant with propensity to use dietary supplements (p= 1.68 × 10–8). With respect to the same OE phenotype in the gene-based analysis, we identified SDCCAG8(EUR + AFR z= 4.69, p= 10–6), which was previously associated with educational attainment, risk-taking behaviors, and schizophrenia. In addition, rs201123820 showed a genome-wide significant difference between OD cases and unexposed controls (AFR z= 5.55, p= 2.9 × 10–8) and a significant association with musculoskeletal disorders in the UK Biobank (p= 4.88 × 10–7). A polygenic risk score (PRS) based on a GWAS of risk-tolerance (n= 466,571) was positively associated with OD (OD vs. unexposed controls, p= 8.1 × 10–5; OD cases vs. exposed controls, p= 0.054) and OE (exposed vs. unexposed controls, p= 3.6 × 10–5). A PRS based on a GWAS of neuroticism (n= 390,278) was positively associated with OD (OD vs. unexposed controls, p= 3.2 × 10–5; OD vs. exposed controls, p= 0.002) but not with OE (p= 0.67). Our analyses highlight the difference between dependence and exposure and the importance of considering the definition of controls in studies of addiction.

Genomewide association studies (GWAS) have begun to identify loci related to alcohol consumption, but little is known about whether this genetic propensity overlaps with specific indices of problem drinking in ascertained samples. In 6,731 European Americans who had been exposed to alcohol, we examined whether polygenic risk scores (PRS) from a GWASof weekly alcohol consumption in the UKBiobank predicted variance in 6 alcohol‐related phenotypes: alcohol use, maximum drinks within 24 hours (MAXD), total score on the Self‐Rating of the Effects of Ethanol Questionnaire (SRE‐T), DSM‐IV alcohol dependence (DSM4AD), DSM‐5 alcohol use disorder symptom counts (DSM5AUDSX), and reduction/cessation of problematic drinking. We also examined the extent to which an single nucleotide polymorphism (rs1229984) in ADH1B, which is strongly associated with both alcohol consumption and dependence, contributed to the polygenic association with these phenotypes and whether PRSinteracted with sex, age, or family history of alcoholism to predict alcohol‐related outcomes. We performed mixed‐effect regression analyses, with family membership and recruitment site included as random effects, as well as survival modeling of age of onset of DSM4AD. PRS for alcohol consumption significantly predicted variance in 5 of the 6 outcomes: alcohol use (Δmarginal R2= 1.39%, Δ area under the curve [AUC] = 0.011), DSM4AD (Δmarginal R2= 0.56%; ΔAUC = 0.003), DSM5AUDSX (Δmarginal R2= 0.49%), MAXD(Δmarginal R2= 0.31%), and SRE‐T (Δmarginal R2= 0.22%). PRSwere also associated with onset of DSM4AD (hazard ratio = 1.11, p = 2.08e−5). The inclusion of rs1229984 attenuated the effects of the alcohol consumption PRS, particularly for DSM4AD and DSM5AUDSX, but the PRScontinued to exert an independent effect for all 5 alcohol measures (Δmarginal R2after controlling for ADH1B= 0.14 to 1.22%). Interactions between PRSand sex, age, or family history were nonsignificant. Genetic propensity for typical alcohol consumption was associated with alcohol use and was also associated with 4 of the additional 5 outcomes, though the variance explained in this sample was modest. Future GWASthat focus on the multifaceted nature of AUD, which goes beyond consumption, might reveal additional information regarding the polygenic underpinnings of problem drinking. The extent to which polygenic liability for alcohol consumption (i.e., drinks per week) overlaps with more severe drinking behaviors, such as maximum drinks consumed, is unclear. We examined the associations between a polygenic score for alcohol consumption measured in the UK Biobank, a population cohort, and several measures of regular and problematic alcohol use in an ascertained sample. Genetic propensity for consumption was associated with 5 of 6 outcomes, but the variance explained in this sample was modest.

Liability to alcohol dependence (AD) is heritable, but little is known about its complex polygenic architecture or its genetic relationship with other disorders. To discover loci associated with AD and characterize the relationship between AD and other psychiatric and behavioral outcomes, we carried out the largest genome-wide association study to date of DSM-IV-diagnosed AD. Genome-wide data on 14,904 individuals with AD and 37,944 controls from 28 case–control and family-based studies were meta-analyzed, stratified by genetic ancestry (European, n= 46,568; African, n= 6,280). Independent, genome-wide significant effects of different ADH1Bvariants were identified in European (rs1229984; P= 9.8 × 10–13) and African ancestries (rs2066702; P= 2.2 × 10–9). Significant genetic correlations were observed with 17 phenotypes, including schizophrenia, attention deficit–hyperactivity disorder, depression, and use of cigarettes and cannabis. The genetic underpinnings of AD only partially overlap with those for alcohol consumption, underscoring the genetic distinction between pathological and nonpathological drinking behaviors.

Previous studies indicate that low initial sensitivity to alcohol may be a risk factor for later alcohol misuse. Evidence suggests that initial sensitivity is influenced by genetic factors, but few molecular genetic studies have been reported. We conducted a meta‐analysis of 2 population‐based genome‐wide association studies of the Self‐Rating of the Effects of Alcohol scale. Our final sample consisted of 7,339 individuals (82.3% of European descent; 59.2% female) who reported having used alcohol at least 5 times. In addition, we estimated single nucleotide polymorphism (SNP)‐based heritability and conducted a series of secondary aggregate genetic analyses. No individual locus reached genome‐wide significance. Gene and set based analyses, both overall and using tissue‐specific expression data, yielded largely null results, and genes previously implicated in alcohol problems and consumption were overall not associated with initial sensitivity. Only 1 gene set, related to hormone signaling and including core clock genes, survived correction for multiple testing. A meta‐analysis of SNP‐based heritability resulted in a modest estimate of hSNP2= 0.19 (SE= 0.10), though this was driven by 1 sample (N= 3,683, hSNP2= 0.36, SE = 0.14, p= 0.04). No significant genetic correlations with other relevant outcomes were observed. Findings yielded only modest support for a genetic component underlying initial alcohol sensitivity. Results suggest that its biological underpinnings may diverge somewhat from that of other alcohol outcomes and may be related to core clock genes or other aspects of hormone signaling. Larger samples, ideally of prospectively assessed samples, are likely necessary to improve gene identification efforts and confirm the current findings. Initial sensitivity to alcohol is associated with later problematic alcohol‐related outcomes. The current study found evidence of aggregate genetic influences on initial sensitivity, though no individual SNP met genome‐wide significance criteria. Further analyses suggest that the biology of initial sensitivity may diverge from that of other alcohol outcomes. As with other complex traits, how initial sensitivity is assessed is likely critical to the identification of robust genetic signals.

IMPORTANCE: Parkinson disease (PD) is a progressive neurodegenerative disease for which susceptibility is linked to genetic and environmental risk factors. OBJECTIVE: To identify genetic variants contributing to disease risk in familial PD. DESIGN, SETTING, AND PARTICIPANTS: A 2-stage study design that included a discovery cohort of families with PD and a replication cohort of familial probands was used. In the discovery cohort, rare exonic variants that segregated in multiple affected individuals in a family and were predicted to be conserved or damaging were retained. Genes with retained variants were prioritized if expressed in the brain and located within PD-relevant pathways. Genes in which prioritized variants were observed in at least 4 families were selected as candidate genes for replication in the replication cohort. The setting was among individuals with familial PD enrolled from academic movement disorder specialty clinics across the United States. All participants had a family history of PD. MAIN OUTCOMES AND MEASURES: Identification of genes containing rare, likely deleterious, genetic variants in individuals with familial PD using a 2-stage exome sequencing study design. RESULTS: The 93 individuals from 32 families in the discovery cohort (49.5% [46 of 93] female) had a mean (SD) age at onset of 61.8 (10.0) years. The 49 individuals with familial PD in the replication cohort (32.6% [16 of 49] female) had a mean (SD) age at onset of 50.1 (15.7) years. Discovery cohort recruitment dates were 1999 to 2009, and replication cohort recruitment dates were 2003 to 2014. Data analysis dates were 2011 to 2015. Three genes containing a total of 13 rare and potentially damaging variants were prioritized in the discovery cohort. Two of these genes (TNK2 and TNR) also had rare variants that were predicted to be damaging in the replication cohort. All 9 variants identified in the 2 replicated genes in 12 families across the discovery and replication cohorts were confirmed via Sanger sequencing. CONCLUSIONS AND RELEVANCE: TNK2 and TNR harbored rare, likely deleterious, variants in individuals having familial PD, with similar findings in an independent cohort. To our knowledge, these genes have not been previously associated with PD, although they have been linked to critical neuronal functions. Further studies are required to confirm a potential role for these genes in the pathogenesis of PD.

Common variants have been identified using genome-wide association studies which contribute to intracranial aneurysms (IA) susceptibility. However, it is clear that the variants identified to date do not account for the estimated genetic contribution to disease risk.

Genomewide association studies have identified novel genetic factors that contribute to intracranial aneurysm (IA) susceptibility. We sought to confirm previously reported loci, to identify novel risk factors, and to evaluate the contribution of these factors to familial and sporadic IA.

The purpose of this study was to replicate the previous association of single nucleotide polymorphisms (SNPs) with risk of intracranial aneurysm (IA) and to examine the relationship of smoking with these variants and the risk of IA.

Background: The high and low alcohol preferring (HAP1 and LAP1) mouse lines were selectively bred for differences in alcohol intake. The HAP1 and LAP1 mice are essentially noninbred lines that originated from the outbred colony of HS/Ibg mice, a heterogeneous stock developed from intercrossing 8 inbred strains of mice.

Risk for both intracranial aneurysms (IAs) and aortic aneurysms (AAs) is thought to be heritable with mounting evidence for genetic predisposition. The concept of shared risk for these conditions is challenged by differences in age of diagnosis and demographic characteristics. We performed a genomewide linkage analysis in multiplex families with both IA and AA from the Familial Intracranial Aneurysm study.

Evidence supports a substantial genetic contribution to the risk of intracranial aneurysm (IA). The purpose of this study was to identify chromosomal regions likely to harbor genes that contribute to the risk of IA.

The Alox15gene was recently identified as a negative regulator of peak BMD in mice. Polymorphisms in human ALOX12, but not ALOX15, were significantly associated with spine BMD in white men and women, suggesting that ALOX12may contribute to normal variation in BMD.Introduction:Osteoporosis is a complex disease with both genetic and environmental risk factors. A major determinant of osteoporosis is peak BMD, which is a highly heritable trait. Recently, the arachidonate 15‐lipoxygenase(Alox15) gene was identified as a negative regulator of peak BMD in mice.Materials and Methods:To assess the contribution of lipoxygenase genes to normal BMD variation in healthy white men and women, we performed population‐ and family‐based association studies of two arachidonate lipoxygenase genes: ALOX15, which is the human homolog of mouse Alox15, and ALOX12, which is functionally similar to Alox15. Single nucleotide polymorphisms (SNPs) distributed across the two genes were genotyped. BMD was measured at the femoral neck and lumbar spine in 411 men 18–61 years of age and 1291 premenopausal women 20–50 years of age.Results:Moderate evidence of association was found between spine BMD and six SNPs in the ALOX12gene in both men and women (p= 0.0052–0.050). Furthermore, the most common SNP haplotype in ALOX12showed evidence of significant association with high spine BMD in men (p= 0.0083), whereas the second most common haplotype was associated with high spine BMD in women (p= 0.0081).Conclusions:Polymorphisms in the ALOX12gene may contribute to normal variation in spine BMD.

The Alox15gene was recently identified as a negative regulator of peak BMD in mice. Polymorphisms in human ALOX12, but not ALOX15, were significantly associated with spine BMD in white men and women, suggesting that ALOX12may contribute to normal variation in BMD.

The role of the LRP5gene in rare BMD‐related traits has recently been shown. We tested whether variation in this gene might play a role in normal variation in peak BMD. Association between SNPs in LRP5and hip and spine BMD was measured in 1301 premenopausal women. Only a small proportion of the BMD variation was attributable to LRP5in our sample.

The role of the LRP5gene in rare BMD‐related traits has recently been shown. We tested whether variation in this gene might play a role in normal variation in peak BMD. Association between SNPs in LRP5and hip and spine BMD was measured in 1301 premenopausal women. Only a small proportion of the BMD variation was attributable to LRP5in our sample.Introduction:Mutations in the low‐density lipoprotein receptor‐related protein 5(LRP5) gene have been implicated as the cause of multiple distinct BMD‐related rare Mendelian phenotypes. We sought to examine whether the LRP5gene contributes to the observed variation in peak BMD in the normal population.Materials and Methods:We genotyped 12 single nucleotide polymorphisms (SNPs) in LRP5using allele‐specific PCR and mass spectrometry methods. Linkage disequilibrium between the genotyped LRP5SNPs was measured. We tested for association between these SNPs and both hip and spine BMD (adjusted for age and body weight) in 1301 healthy premenopausal women who took part in a sibling pair study aimed at identifying the genes underlying peak bone mass. Our study used both population‐based (ANOVA) and family‐based (quantitative transmission disequilibrium test) association methodology.Results and Conclusions:The linkage disequilibrium pattern and haplotype block structure within the LRP5gene were consistent with that observed in other studies. Although significant evidence of association was found between LRP5SNPs and both hip and spine BMD, only a small proportion of the total variation in these phenotypes was accounted for. The genotyped SNPs accounted for ∼0.8% of the variation in femoral neck BMD and 1.1% of the variation in spine BMD. Results from our sample suggest that natural variation in and around LRP5is not a major contributor to the observed variability in peak BMD at either the femoral neck or lumbar spine in white women.

To explore the degree to which stratification can cause spurious positive association results, we tested for association between BMD and 373 genetic markers using 381 white and 126 black females. The rate of positive results doubled as the proportion of stratification increased, showing the importance of controlling for stratification in association studies.

To explore the degree to which stratification can cause spurious positive association results, we tested for association between BMD and 373 genetic markers using 381 white and 126 black females. The rate of positive results doubled as the proportion of stratification increased, showing the importance of controlling for stratification in association studies.Introduction:Population‐based association studies are commonly used to test the relationship between polymorphisms in a candidate gene and a disease or trait of interest. Although the collection of samples for this type of study design is relatively cost‐effective, the statistical analysis may be susceptible to false positive results because of the effects of population stratification. Such results may occur when the underlying populations differ in both the polymorphism allele frequency and mean trait value.Materials and Methods:To explore the degree to which stratification can cause spurious positive association results, we analyzed femoral neck BMD data from an unrelated sample of 381 white and 126 black premenopausal females. As part of a previous genome screen, 373 microsatellite markers had been genotyped for each individual. For simplicity of interpretation, each multiallelic marker was reduced to a biallelic marker, with the most common allele as one allele and all other alleles combined as the second allele. As expected, the black women differed substantially for marker allele frequencies and had significantly higher mean femoral neck BMD than their white counterparts. Random subsets of the white and black samples were sampled, with increasing proportions of stratification (0%, 1%, 2%, 5%, 10%, 15%, and 20% black subjects) in the total analyzed sample. ANOVA was used to test for association between the recoded marker and femoral neck BMD.Results and Conclusions:The rate of positive results for the association test were observed to double as the proportion of stratification increased, with substantial increases in the frequency of false positives even for stratification proportions as small as 2‐5%. These results show the importance of controlling for stratification when the trait and the polymorphism allele frequency differ between the races.

Genome-wide association studies have been conducted in alcohol use disorder (AUD), and they permit the use of polygenic risk scores (PRSs), in combination with clinical variables, to predict the onset of AUD in vulnerable populations.