Genome-wide Association Studies in Ancestrally Diverse Populations: Opportunities, Methods, Pitfalls, and Recommendations.

Genome-wide association studies (GWASs) have focused primarily on populations of European descent, but it is essential that diverse populations become better represented. Increasing diversity among study participants will advance our understanding of genetic architecture in all populations and ensure that genetic research is broadly applicable. To facilitate and promote research in multi-ancestry and admixed cohorts, we outline key methodological considerations and highlight opportunities, challenges, solutions, and areas in need of development. Despite the perception that analyzing genetic data from diverse populations is difficult, it is scientifically and ethically imperative, and there is an expanding analytical toolbox to do it well.

Correlates of suicidal behaviors and genetic risk among United States veterans with schizophrenia or bipolar I disorder.

Persons diagnosed with schizophrenia (SCZ) or bipolar I disorder (BPI) are at high risk for self-injurious behavior, suicidal ideation, and suicidal behaviors (SB). Characterizing associations between diagnosed health problems, prior pharmacological treatments, and polygenic scores (PGS) has potential to inform risk stratification. We examined self-reported SB and ideation using the Columbia Suicide Severity Rating Scale (C-SSRS) among 3,942 SCZ and 5,414 BPI patients receiving care within the Veterans Health Administration (VHA). These cross-sectional data were integrated with electronic health records (EHRs), and compared across lifetime diagnoses, treatment histories, follow-up screenings, and mortality data. PGS were constructed using available genomic data for related traits. Genome-wide association studies were performed to identify and prioritize specific loci. Only 20% of the veterans who reported SB had a corroborating ICD-9/10 EHR code. Among those without prior SB, more than 20% reported new-onset SB at follow-up. SB were associated with a range of additional clinical diagnoses, and with treatment with specific classes of psychotropic medications (e.g., antidepressants, antipsychotics, etc.). PGS for externalizing behaviors, smoking initiation, suicide attempt, and major depressive disorder were associated with SB. The GWAS for SB yielded no significant loci. Among individuals with a diagnosed mental illness, self-reported SB were strongly associated with clinical variables across several EHR domains. Analyses point to sequelae of substance-related and psychiatric comorbidities as strong correlates of prior and subsequent SB. Nonetheless, past SB was frequently not documented in health records, underscoring the value of regular screening with direct, in-person assessments, especially among high-risk individuals.

Determining the stability of genome-wide factors in BMI between ages 40 to 69 years.

Genome-wide association studies (GWAS) have successfully identified common variants associated with BMI. However, the stability of aggregate genetic variation influencing BMI from midlife and beyond is unknown. By analysing 165,717 men and 193,073 women from the UKBiobank, we performed BMI GWAS on six independent five-year age intervals between 40 and 72 years. We then applied genomic structural equation modeling to test competing hypotheses regarding the stability of genetic effects for BMI. LDSR genetic correlations between BMI assessed between ages 40 to 73 were all very high and ranged 0.89 to 1.00. Genomic structural equation modeling revealed that molecular genetic variance in BMI at each age interval could not be explained by the accumulation of any age-specific genetic influences or autoregressive processes. Instead, a common set of stable genetic influences appears to underpin genome-wide variation in BMI from middle to early old age in men and women alike.

Associations between polygenic liability to psychopathology and non-suicidal versus suicidal self-injury.

Little is known about how non-suicidal and suicidal self-injury are differentially genetically related to psychopathology and related measures. This research was conducted using the UK Biobank Resource, in participants of European ancestry (N = 2320 non-suicidal self-injury [NSSI] only; N = 2648 suicide attempt; 69.18% female). We compared polygenic scores (PGS) for psychopathology and other relevant measures within self-injuring individuals. Logistic regressions and likelihood ratio tests (LRT) were used to identify PGS that were differentially associated with these outcomes. In a multivariable model, PGS for anorexia nervosa (odds ratio [OR] = 1.07; 95% confidence intervals [CI] 1.01; 1.15) and suicidal behavior (OR = 1.06; 95% CI 1.00; 1.12) both differentiated between NSSI and suicide attempt, while the PGS for other phenotypes did not. The LRT between the multivariable and base models was significant (Chi square = 11.38, df = 2, p = 0.003), and the multivariable model explained a larger proportion of variance (Nagelkerke's pseudo-R2 = 0.028 vs. 0.025). While NSSI and suicidal behavior are similarly genetically related to a range of mental health and related outcomes, genetic liability to anorexia nervosa and suicidal behavior is higher among those reporting a suicide attempt than those reporting NSSI-only. Further elucidation of these distinctions is necessary, which will require a nuanced assessment of suicidal versus non-suicidal self-injury in large samples.

Differences in genetic correlations between posttraumatic stress disorder and alcohol-related problems phenotypes compared to alcohol consumption-related phenotypes.

BACKGROUND: Posttraumatic Stress Disorder (PTSD) tends to co-occur with greater alcohol consumption as well as alcohol use disorder (AUD). However, it is unknown whether the same etiologic factors that underlie PTSD-alcohol-related problems comorbidity also contribute to PTSD- alcohol consumption. METHODS: We used summary statistics from large-scale genome-wide association studies (GWAS) of European-ancestry (EA) and African-ancestry (AA) participants to estimate genetic correlations between PTSD and a range of alcohol consumption-related and alcohol-related problems phenotypes. RESULTS: In EAs, there were positive genetic correlations between PTSD phenotypes and alcohol-related problems phenotypes (e.g. Alcohol Use Disorders Identification Test (AUDIT) problem score) (rGs: 0.132-0.533, all FDR adjusted p < 0.05). However, the genetic correlations between PTSD phenotypes and alcohol consumption -related phenotypes (e.g. drinks per week) were negatively associated or non-significant (rGs: -0.417 to -0.042, FDR adjusted p: <0.05-NS). For AAs, the direction of correlations was sometimes consistent and sometimes inconsistent with that in EAs, and the ranges were larger (rGs for alcohol-related problems: -0.275 to 0.266, FDR adjusted p: NS, alcohol consumption-related: 0.145-0.699, FDR adjusted p: NS). CONCLUSIONS: These findings illustrate that the genetic associations between consumption and problem alcohol phenotypes and PTSD differ in both strength and direction. Thus, the genetic factors that may lead someone to develop PTSD and high levels of alcohol consumption are not the same as those that lead someone to develop PTSD and alcohol-related problems. Discussion around needing improved methods to better estimate heritabilities and genetic correlations in diverse and admixed ancestry samples is provided.

Investigation of convergent and divergent genetic influences underlying schizophrenia and alcohol use disorder.

BACKGROUND: Alcohol use disorder (AUD) and schizophrenia (SCZ) frequently co-occur, and large-scale genome-wide association studies (GWAS) have identified significant genetic correlations between these disorders. METHODS: We used the largest published GWAS for AUD (total cases = 77 822) and SCZ (total cases = 46 827) to identify genetic variants that influence both disorders (with either the same or opposite direction of effect) and those that are disorder specific. RESULTS: We identified 55 independent genome-wide significant single nucleotide polymorphisms with the same direction of effect on AUD and SCZ, 8 with robust effects in opposite directions, and 98 with disorder-specific effects. We also found evidence for 12 genes whose pleiotropic associations with AUD and SCZ are consistent with mediation via gene expression in the prefrontal cortex. The genetic covariance between AUD and SCZ was concentrated in genomic regions functional in brain tissues (p = 0.001). CONCLUSIONS: Our findings provide further evidence that SCZ shares meaningful genetic overlap with AUD.

Genetic and environmental etiology of drinking motives in college students.

BACKGROUND: Drinking motives are robust proximal predictors of alcohol use behaviors and may mediate distinct etiological pathways in the development of alcohol misuse. However, little is known about the genetic and environmental etiology of drinking motives themselves and their potential utility as endophenotypes. METHODS: Here, we leverage a longitudinal study of college students from diverse racial/ethnic backgrounds (phenotypic N = 9889, genotypic N = 4855) to investigate the temporal stability and demographic and environmental predictors of four types of drinking motives (enhancement, social, coping, and conformity). Using genome-wide association study (GWAS) and in silico tools, we characterize their associated genes and genetic variants (single nucleotide polymorphisms or SNPs). RESULTS: Drinking motives were stable across four years of college (ICC >0.74). Some robust environmental predictors of alcohol misuse (parental autonomy granting and peer deviance) were broadly associated with multiple types of drinking motives, while others (e.g., trauma exposure) were type specific. Genome-wide analyses indicated modest SNP-based heritability (14-22%, n.s.) and several suggestive genomic loci that corroborate findings from previous molecular genetic studies (e.g., PECR and SIRT4 genes), indicating possible differences in the genetic etiology of positive versus negative reinforcement drinking motives that align with an internalizing/externalizing typology of alcohol misuse. Coping motives were significantly genetically correlated with alcohol use disorder diagnoses (rg  = 0.71, p = 0.001). However, results from the genetic analyses were largely underpowered to detect significant associations. CONCLUSIONS: Drinking motives show promise as endophenotypes but require further investigation in larger samples to further our understanding of the etiology of alcohol misuse.

Divergent changes: abstinence and higher-frequency substance use increase among racial/ethnic minority young adults during the COVID-19 global pandemic.

BACKGROUND: Identifying factors influencing substance use among racial/ethnic minorities (REM) is important given the disproportionate impact of the COVID-19 pandemic on this population. OBJECTIVES: We examined factors in four domains and hypothesized that poor mental health, negative coping behaviors, negative environmental aspects, and belonging to more vulnerable social groups would be associated with increased substance use during the pandemic. METHODS: Multiple regression was applied to longitudinal data from a college sample assessed prior (fall 2017 to spring 2019) and during (spring 2020) the pandemic (n= 323; 81.5% cisgender women; 34.5% African-American, 36.1% Asian-American, 15.5% Hispanic/Latinx, 11.8% multi-racial) to identify factors predicting current alcohol, cannabis, and nicotine use frequency (spring 2020) and change in frequency of use between springs 2019 and 2020. RESULTS: While infrequent substance use (monthly or less) decreased during the pandemic, abstinence rates increased (alcohol 39%; cannabis 18%; nicotine 18%) and higher-frequency alcohol use increased (207%-1600% 2-3 times+/week) compared to spring 2019. The strongest protective factor was change in living situation during the pandemic, associated with lower current alcohol and cannabis use. Risk factors included a history of trouble with police and impulsivity since the pandemic, both associated with higher current and increased alcohol and cannabis use. REM did not differ on most factors and the outcomes. However, a higher percentage of Asian-Americans than other REM reported living situation changes. CONCLUSION: Substance use rates diverged during the pandemic, with both increased abstinence and higher-frequency use, attributed mostly to mental health and environmental domain factors with few REM differences.

Leveraging genome-wide data to investigate differences between opioid use vs. opioid dependence in 41,176 individuals from the Psychiatric Genomics Consortium.

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 SLC30A9 and BEND4 in 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.

Contributions of common genetic variants to risk of schizophrenia among individuals of African and Latino ancestry.

Schizophrenia is a common, chronic and debilitating neuropsychiatric syndrome affecting tens of millions of individuals worldwide. While rare genetic variants play a role in the etiology of schizophrenia, most of the currently explained liability is within common variation, suggesting that variation predating the human diaspora out of Africa harbors a large fraction of the common variant attributable heritability. However, common variant association studies in schizophrenia have concentrated mainly on cohorts of European descent. We describe genome-wide association studies of 6152 cases and 3918 controls of admixed African ancestry, and of 1234 cases and 3090 controls of Latino ancestry, representing the largest such study in these populations to date. Combining results from the samples with African ancestry with summary statistics from the Psychiatric Genomics Consortium (PGC) study of schizophrenia yielded seven newly genome-wide significant loci, and we identified an additional eight loci by incorporating the results from samples with Latino ancestry. Leveraging population differences in patterns of linkage disequilibrium, we achieve improved fine-mapping resolution at 22 previously reported and 4 newly significant loci. Polygenic risk score profiling revealed improved prediction based on trans-ancestry meta-analysis results for admixed African (Nagelkerke's R2 = 0.032; liability R2 = 0.017; P < 10-52), Latino (Nagelkerke's R2 = 0.089; liability R2 = 0.021; P < 10-58), and European individuals (Nagelkerke's R2 = 0.089; liability R2 = 0.037; P < 10-113), further highlighting the advantages of incorporating data from diverse human populations.

The Genetics of Major Depression: Perspectives on the State of Research and Opportunities for Precision Medicine.

Major depression (MD) is a leading cause of disability worldwide; it arises from the action and interaction between genetic and environmental factors, and is often comorbid with other psychiatric and medical conditions. To date, upwards of 100 genetic loci have been associated with MD, giving clues to biological underpinnings. Although recent progress has yielded modest insight into the genetic architecture of MD, most studies have been in populations with European ancestry, seriously limiting precision medicine efforts. Broadening diversity of study populations will empower genomic research by expanding discovery and enhancing our understanding of the role of genomic variation in disease etiology. To fully realize the potential of pharmacogenetics and precision medicine, we will need to address the major gaps in our knowledge of the genetic and environmental risk architecture of MD across ancestries, including sex differences, to improve etiologic understanding, diagnosis, prevention, and treatment for all.

Pathway-based polygene risk for severe depression implicates drug metabolism in CONVERGE.

BACKGROUND: The Psychiatric Genomics Consortium (PGC) has made major advances in the molecular etiology of MDD, confirming that MDD is highly polygenic. Pathway enrichment results from PGC meta-analyses can also be used to help inform molecular drug targets. Prior to any knowledge of molecular biomarkers for MDD, drugs targeting molecular pathways (MPs) proved successful in treating MDD. It is possible that examining polygenicity within specific MPs implicated in MDD can further refine molecular drug targets. METHODS: Using a large case-control GWAS based on low-coverage whole genome sequencing (N = 10 640) in Han Chinese women, we derived polygenic risk scores (PRS) for MDD and for MDD specific to each of over 300 MPs previously shown to be relevant to psychiatric diagnoses. We then identified sets of PRSs, accounting for critical covariates, significantly predictive of case status. RESULTS: Over and above global MDD polygenic risk, polygenic risk within the GO: 0017144 drug metabolism pathway significantly predicted recurrent depression after multiple testing correction. Secondary transcriptomic analysis suggests that among genes in this pathway, CYP2C19 (family of Cytochrome P450) and CBR1 (Carbonyl Reductase 1) might be most relevant to MDD. Within the cases, pathway-based risk was additionally associated with age at onset of MDD. CONCLUSIONS: Results indicate that pathway-based risk might inform etiology of recurrent major depression. Future research should examine whether polygenicity of the drug metabolism gene pathway has any association with clinical presentation or treatment response. We discuss limitations to the generalizability of these preliminary findings, and urge replication in future research.

Evidence of causal effect of major depression on alcohol dependence: findings from the psychiatric genomics consortium.

BACKGROUND: Despite established clinical associations among major depression (MD), alcohol dependence (AD), and alcohol consumption (AC), the nature of the causal relationship between them is not completely understood. We leveraged genome-wide data from the Psychiatric Genomics Consortium (PGC) and UK Biobank to test for the presence of shared genetic mechanisms and causal relationships among MD, AD, and AC. METHODS: Linkage disequilibrium score regression and Mendelian randomization (MR) were performed using genome-wide data from the PGC (MD: 135 458 cases and 344 901 controls; AD: 10 206 cases and 28 480 controls) and UK Biobank (AC-frequency: 438 308 individuals; AC-quantity: 307 098 individuals). RESULTS: Positive genetic correlation was observed between MD and AD (rgMD-AD = + 0.47, P = 6.6 × 10-10). AC-quantity showed positive genetic correlation with both AD (rgAD-AC quantity = + 0.75, P = 1.8 × 10-14) and MD (rgMD-AC quantity = + 0.14, P = 2.9 × 10-7), while there was negative correlation of AC-frequency with MD (rgMD-AC frequency = -0.17, P = 1.5 × 10-10) and a non-significant result with AD. MR analyses confirmed the presence of pleiotropy among these four traits. However, the MD-AD results reflect a mediated-pleiotropy mechanism (i.e. causal relationship) with an effect of MD on AD (beta = 0.28, P = 1.29 × 10-6). There was no evidence for reverse causation. CONCLUSION: This study supports a causal role for genetic liability of MD on AD based on genetic datasets including thousands of individuals. Understanding mechanisms underlying MD-AD comorbidity addresses important public health concerns and has the potential to facilitate prevention and intervention efforts.

International Society of Psychiatric Genetics Ethics Committee: Issues facing us.

Psychiatric genetics research is improving our understanding of the biological underpinnings of neurodiversity and mental illness. Using psychiatric genetics in ways that maximize benefits and minimize harms to individuals and society depends largely on how the ethical, legal, and social implications (ELSI) of psychiatric genetics are managed. The International Society of Psychiatric Genetics (ISPG) is the largest international organization dedicated to psychiatric genetics. Given its history, membership, and international reach, we believe the ISPG is well-equipped to contribute to the resolution of these ELSI challenges. As such, we recently created the ISPG Ethics Committee, an interdisciplinary group comprised of psychiatric genetics researchers, clinical geneticists, genetic counselors, mental health professionals, patients, patient advocates, bioethicists, and lawyers. This article highlights key ELSI challenges identified by the ISPG Ethics Committee to be of paramount importance for the ethical translation of psychiatric research into society in three contexts: research settings, clinical settings, and legal proceedings. For each of these arenas, we identify and discuss pressing psychiatric genetics ELSI dilemmas that merit attention and require action. The goal is to increase awareness about psychiatric genetics ELSI issues and encourage dialogue and action among stakeholders.

Replication of the Interaction of PRKG1 and Trauma Exposure on Alcohol Misuse in an Independent African American Sample.

In the present study, we sought to replicate recent findings of Polimanti et al. (2017), who conducted a genome-wide gene-by-environment interaction study (GEWIS) and identified a gene-by-trauma interaction that predicts alcohol misuse among African Americans.  Consistent with the findings published by Polimanti and colleagues, results of the current study demonstrated an interaction effect, b = 0.41, of trauma exposure and rs1729578 in the intron of PRKG1 on alcohol misuse in a subsample of ancestral African Americans. The minor allele (rs1729578*C) was positively associated with increased alcohol use disorder symptoms in trauma-exposed subjects and negatively associated in non-trauma-exposed subjects.  This effect, however, was only significant for one out of three alcohol outcome measures we investigated, suggesting the interaction may be most salient when predicting higher severity of alcohol misuse. Additionally, the effect did not remain significant after we accounted for testing the effect on three different outcome variables. Also in line with the original study, the gene-by-environment effect was not demonstrated among the ancestral European subsample.  The findings suggest this gene variant may increase an individual's susceptibility to environmental influences, both adverse and supportive.

Deep Sequencing of 71 Candidate Genes to Characterize Variation Associated with Alcohol Dependence.

BACKGROUND: Previous genomewide association studies (GWASs) have identified a number of putative risk loci for alcohol dependence (AD). However, only a few loci have replicated and these replicated variants only explain a small proportion of AD risk. Using an innovative approach, the goal of this study was to generate hypotheses about potentially causal variants for AD that can be explored further through functional studies. METHODS: We employed targeted capture of 71 candidate loci and flanking regions followed by next-generation deep sequencing (mean coverage 78X) in 806 European Americans. Regions included in our targeted capture library were genes identified through published GWAS of alcohol, all human alcohol and aldehyde dehydrogenases, reward system genes including dopaminergic and opioid receptors, prioritized candidate genes based on previous associations, and genes involved in the absorption, distribution, metabolism, and excretion of drugs. We performed single-locus tests to determine if any single variant was associated with AD symptom count. Sets of variants that overlapped with biologically meaningful annotations were tested for association in aggregate. RESULTS: No single, common variant was significantly associated with AD in our study. We did, however, find evidence for association with several variant sets. Two variant sets were significant at the q-value <0.10 level: a genic enhancer for ADHFE1 (p = 1.47 × 10-5 ; q = 0.019), an alcohol dehydrogenase, and ADORA1 (p = 5.29 × 10-5 ; q = 0.035), an adenosine receptor that belongs to a G-protein-coupled receptor gene family. CONCLUSIONS: To our knowledge, this is the first sequencing study of AD to examine variants in entire genes, including flanking and regulatory regions. We found that in addition to protein coding variant sets, regulatory variant sets may play a role in AD. From these findings, we have generated initial functional hypotheses about how these sets may influence AD.

Age of onset and family history as indicators of polygenic risk for major depression.

BACKGROUND: The extent to which earlier age of onset (AO) is a reflection of increased genetic risk for major depression (MD) is still unknown. Previous biometrical research has provided mixed empirical evidence for the genetic overlap of AO with MD. If AO is demonstrated to be relevant to molecular polygenic risk for MD, incorporation of AO as a phenotype could enhance future genetic studies. METHODS: This research estimated the SNP-based heritability of AO in the China, Oxford and VCU Experimental Research on Genetic Epidemiology (CONVERGE) case-control sample (N = 9,854; MD case, n = 4,927). Common single nucleotide polymorphism heritability of MD was also examined across both high and low median-split AO groups, and best linear unbiased predictor (BLUP) scores of polygenic risk, in split-halves, were used to predict AO. Distributions of genetic risk across early and late AO were compared, and presence of self-reported family history (FH) of MD was also examined as a predictor of AO. RESULTS: AO was not significantly heritable and polygenic risk derived from the aggregated effects of common genetic variants did not significantly predict AO in any analysis. AO was modestly but significantly lower in cases with a first-degree genetic FH of MD. CONCLUSIONS: Findings indicate that AO is associated with greater self-reported genetic risk for MD in cases, yet not associated with common variant polygenic risk for MD. Future studies of early MD may benefit more from the examination of important moderating variables such as early life events.

The utility of empirically assigning ancestry groups in cross-population genetic studies of addiction.

BACKGROUND AND OBJECTIVES: Given moderate heritability and significant heterogeneity among addiction phenotypes, successful genome-wide association studies (GWAS) are expected to need very large samples. As sample sizes grow, so can genetic diversity leading to challenges in analyzing these data. Methods for empirically assigning individuals to genetically informed ancestry groups are needed. METHODS: We describe a strategy for empirically assigning ancestry groups in ethnically diverse GWAS data including extensions of principal component analysis (PCA) and population matching through minimum Mahalanobis distance. We apply these methods to data from Spit for Science (S4S): the University Student Survey, a study following college students longitudinally that includes genetic and environmental data on substance use and mental health (n = 7,603). RESULTS: The genetic-based population assignments for S4S were 48.7% European, 22.5% African, 10.4% Americas, 9.2% East Asian, and 9.2% South Asian descent. Self-reported census categories "More than one race" and "Unknown"as well as "Hawaiian/Pacific Islander" and "American-Indian/Native Alaskan" were empirically assigned representing a +9% sample retention over conventional methods. Although there was high concordance between self-reported race and empirical population-match (+.924), there was reduction in variance for most ancestry PCs for genetic-based population assignments. CONCLUSIONS: We were able to create more genetically homogenous groups and reduce sample and marker loss through cross-ancestry meta-analysis, potentially increasing power to detect etiologically relevant variation. Our approach provides a framework for empirically assigning genetic ancestry groups which can be applied to other ethnically diverse genetic studies. SCIENTIFIC SIGNIFICANCE: Given the important public health impact and demonstrable gains in statistical power from studying diverse populations, empirically sound practices for genetic studies are needed. (Am J Addict 2017;26:494-501).

CHRONICITY OF DEPRESSION AND MOLECULAR MARKERS IN A LARGE SAMPLE OF HAN CHINESE WOMEN.

BACKGROUND: Major depressive disorder (MDD) has been associated with changes in mean telomere length and mitochondrial DNA (mtDNA) copy number. This study investigates if clinical features of MDD differentially impact these molecular markers. METHODS: Data from a large, clinically ascertained sample of Han Chinese women with recurrent MDD were used to examine whether symptom presentation, severity, and comorbidity were related to salivary telomere length and/or mtDNA copy number (maximum N = 5,284 for both molecular and phenotypic data). RESULTS: Structural equation modeling revealed that duration of longest episode was positively associated with mtDNA copy number, while earlier age of onset of most severe episode and a history of dysthymia were associated with shorter telomeres. Other factors, such as symptom presentation, family history of depression, and other comorbid internalizing disorders, were not associated with these molecular markers. CONCLUSIONS: Chronicity of depressive symptoms is related to more pronounced telomere shortening and increased mtDNA copy number among individuals with a history of recurrent MDD. As these molecular markers have previously been implicated in physiological aging and morbidity, individuals who experience prolonged depressive symptoms are potentially at greater risk of adverse medical outcomes.

Deep Sequencing of Three Loci Implicated in Large-Scale Genome-Wide Association Study Smoking Meta-Analyses.

INTRODUCTION: Genome-wide association study meta-analyses have robustly implicated three loci that affect susceptibility for smoking: CHRNA5\CHRNA3\CHRNB4, CHRNB3\CHRNA6 and EGLN2\CYP2A6. Functional follow-up studies of these loci are needed to provide insight into biological mechanisms. However, these efforts have been hampered by a lack of knowledge about the specific causal variant(s) involved. In this study, we prioritized variants in terms of the likelihood they account for the reported associations. METHODS: We employed targeted capture of the CHRNA5\CHRNA3\CHRNB4, CHRNB3\CHRNA6, and EGLN2\CYP2A6 loci and flanking regions followed by next-generation deep sequencing (mean coverage 78×) to capture genomic variation in 363 individuals. We performed single locus tests to determine if any single variant accounts for the association, and examined if sets of (rare) variants that overlapped with biologically meaningful annotations account for the associations. RESULTS: In total, we investigated 963 variants, of which 71.1% were rare (minor allele frequency < 0.01), 6.02% were insertion/deletions, and 51.7% were catalogued in dbSNP141. The single variant results showed that no variant fully accounts for the association in any region. In the variant set results, CHRNB4 accounts for most of the signal with significant sets consisting of directly damaging variants. CHRNA6 explains most of the signal in the CHRNB3\CHRNA6 locus with significant sets indicating a regulatory role for CHRNA6. Significant sets in CYP2A6 involved directly damaging variants while the significant variant sets suggested a regulatory role for EGLN2. CONCLUSIONS: We found that multiple variants implicating multiple processes explain the signal. Some variants can be prioritized for functional follow-up.