Biology subjects

Polimanti, R.

Publications and source records attributed to Polimanti, R..

15 recordsLinked to original sources

bioRxiv2024

Multi-ancestry tandem repeat association study of hair color using exome-wide sequencing

Hair colour variation is influenced by hundreds of positions across the human genome but this genetic contribution has only been narrowly explored. Genome-wide association studies identified single nucleotide polymorphisms (SNPs) influencing hair colour but the biology underlying these associations is challenging to interpret. We report 16 tandem repeats (TRs) with effects on different models of hair colour plus two TRs associated with hair colour in diverse ancestry groups. Several of these TRs expand or contract amino acid coding regions of their localized protein such that structure, and by extension function, may be altered. We also demonstrate that independent of SNP variation, these TRs can be used to great an additive polygenic score that predicts darker hair colour. This work adds to the growing body of evidence regarding TR influence on human traits with relatively large and independent effects relative to surrounding SNP variation.

genomics↗

bioRxiv2022

Declining autozygosity over time: an exploration in over 1 million individuals from three diverse cohorts

We hypothesized that overall autozygosity is decreasing over generational time. In this report, we present data that partially support this hypothesis from three large cohorts of diverse ancestries, two from the US (All of Us and the Million Veteran Program, N=82,474 and 622,497, respectively) and one from the UK (UK Biobank, N=380,899). Our results from a mixed-effect meta-analysis demonstrate an overall trend of decreasing autozygosity over generational time (meta-analyzed slope=-0.029, se=0.009, p=6.03e-4). Using a chi-square difference test, we determined that a model including an ancestry-by-country interaction term fit the data best, indicating that ancestry differences in this trend differ by country. We found further evidence to suggest a difference between the US and UK cohorts by meta-analyzing within country, observing a significant negative estimate in the US cohorts (meta-analyzed slope=-0.058, se=0.015, p=1.50e-4) but a non-significant estimate in the UK (meta-analyzed slope=-0.001, se=0.008, p=0.945). We also found that the association between autozygosity and year of birth in the overall meta-analysis was substantially attenuated when accounting for educational attainment and income (meta-analyzed slope=-0.011, se=0.008, p=0.167), suggesting that increases in education and income may partially account for decreasing levels of autozygosity over time. To our knowledge, this is the largest demonstration of decreasing autozygosity over time in a modern sample (birth years 1904-2003), and we speculate that this trend can be attributed to increases in population size, urbanization and panmixia, with differences in demographic and sociocultural processes leading to country-specific differences in the rate of decline.

genomics↗

bioRxiv2022

The enrichment of self-domestication and neural crest function loci in the heritability of neurodevelopmental disorders is not independent of genomic regulatory functions

Self-domestication could play an important role in contributing to shape the biology of human brain and the predisposition to neurodevelopmental disorders. Leveraging genome-wide data from the Psychiatric Genomics Consortium, we tested the enrichment of self-domestication and neural crest function loci with respect to the heritability of autism spectrum disorder, schizophrenia (SCZ in East Asian and European ancestries, EAS and EUR, respectively), attention-deficit/hyperactivity disorder, obsessive-compulsive disorder, and Tourettes syndrome (TS). Considering only self-domestication and neural-crest-function annotations in the linkage disequilibrium score regression (LDSC) model, our partitioned heritability analysis revealed statistically significant enrichments across all disorders investigated. The estimates of the heritability enrichments for self-domestication loci were similar across neurodevelopmental disorders, ranging from 0.902 (EAS SCZ, p=4.55x10-20) to 1.577 (TS, p=5.85x10-5). Conversely, a wider spectrum of heritability enrichment estimates was present for neural crest function with the highest enrichment observed for TS (enrichment=3.453, p=2.88x10-3) and the lowest for EAS SCZ (enrichment=1.971, p=3.8lx10-3). Although these estimates appear to be strong, the enrichments for self-domestication and neural crest function were null once we included additional annotations related to different genomic features. This indicates that the effect of self-domestication on the polygenic architecture of neurodevelopmental disorders is not independent of other functions of human genome.

genetics↗

bioRxiv2022

Modeling the longitudinal changes of ancestry diversity in the Million Veteran Program

The Million Veteran Program (MVP) participants represent 100 years of US history, including significant social and demographic change over time. Our study assessed two aspects of the MVP: (i) longitudinal changes in population diversity and (ii) how these changes can be accounted for in genome-wide association studies (GWAS). The MVP was divided into five birth cohorts (N-range=123,888 [born from 1943-1947] to 136,699 [born from 1948-1953]). Groups of participants were defined by (i) HARE (harmonized ancestry and race/ethnicity) and (ii) a random-forest clustering approach using the 1000 Genomes Project and the Human Genome Diversity Project (1kGP+HGDP) reference panels (77 world populations representing six continental groups). In these groups, we performed GWASs of height, a trait potentially affected by population stratification. Birth cohorts demonstrate important trends in ancestry diversity over time. More recent HARE-assigned Europeans, Africans, and Hispanics had lower European ancestry proportions than older birth cohorts (0.010<Cohens d<0.259, p<7.80x10-4). Conversely, HARE-assigned East Asians showed an increase in European ancestry proportion over time. In GWAS of height using HARE assignments, genomic inflation due to population stratification was prevalent across all birth cohorts (linkage disequilibrium score regression intercept=1.08{+/-}0.042). The 1kGP+HGDP-based ancestry assignment significantly reduced the population stratification (mean intercept reduction=0.045{+/-}0.007, p<0.05) confounding in the GWAS statistics. This study provides a comprehensive characterization of ancestry diversity of the MVP cohort over time and highlights that more refined modeling of genetic diversity (e.g., the 1kGP+HGDP-based ancestry assignment) can more accurately capture the polygenic architecture of traits and diseases that could be affected by population stratification.

genomics↗

bioRxiv2021

The impact of evolutionary processes in shaping the genetics of complex traits in East Asia and Europe: a specific contribution from Denisovan and Neanderthal introgression

Evidence of how human evolution shaped the polygenicity of human traits and diseases has been extensively studied in populations of European descent. However, limited information is currently available about its impact on other ancestry groups. Here, we investigated how different evolutionary processes affected the common variant heritability of traits and diseases in East Asians. Leveraging genome-wide association statistics from the Biobank Japan (up to 158,284 participants), we assessed natural selection (negative and positive), archaic introgression from Neanderthal and Denisova, and several genomic functional categories with respect to the heritability of physiological and pathological conditions. Similar to reports in European descent populations, the heritability estimates for East Asian traits were ubiquitously enriched for negative selection annotations (false discovery rate, FDR q<0.05). Enrichment of Denisovan introgression was identified in coronary artery disease (1.69-fold enrichment, p=0.003). We followed up these enrichments by conducting a phenome-wide association study (PheWAS) of Denisovan and Neanderthal alleles in participants of six ancestral backgrounds from the UK Biobank. In East Asians, Denisovan-inherited alleles were associated with 22 phenotypes, including metabolic, immunological, cardiovascular, endocrine, and dermatological traits. The strongest association was observed for the Denisovan-inherited locus rs59185462 with rheumatoid arthritis (beta=0.82, p=1.91x10-105). In summary, our study provides the first evidence regarding the impact of evolutionary processes on the genetics of complex traits in worldwide populations, highlighting the specific contribution of Denisovan introgression in East Asian populations.

genetics↗

bioRxiv2020

Natural selection influenced the genetic architecture of brain structure, behavioral and neuropsychiatric traits

Natural selection has shaped the phenotypic characteristics of human populations. Genome-wide association studies (GWAS) have elucidated contributions of thousands of common variants with small effects on an individuals predisposition to complex traits (polygenicity), as well as wide-spread sharing of risk alleles across traits in the human phenome (pleiotropy). It remains unclear how the pervasive effects of natural selection influence polygenicity in brain-related traits. We investigate these effects by annotating the genome with measures of background (BGS) and positive selection, indications of Neanderthal introgression, measures of functional significance including loss-of-function (LoF) intolerant and genic regions, and genotype networks in 75 brain-related traits. Evidence of natural selection was determined using binary annotations of top 2%, 1%, and 0.5% of selection scores genome-wide. We detected enrichment (q<0.05) of SNP-heritability at loci with elevated BGS (7 phenotypes) and in genic (34 phenotypes) and LoF-intolerant regions (67 phenotypes). BGS (top 2%) significantly predicted effect size variance for trait-associated loci ({sigma}2 parameter) in 75 brain-related traits ({beta}=4.39x10-5, p=1.43x10-5, model r2=0.548). By including the number of DSM-5 diagnostic combinations per psychiatric disorder, we substantially improved model fit ({sigma}2 ~ BTop2% x Genic x diagnostic combinations; model r2=0.661). We show that GWAS with larger variance in risk locus effect sizes are collectively predicted by the effects of loci under strong BGS and in regulatory regions of the genome. We further show that diagnostic complexity exacerbates this relationship and perhaps dampens the ability to detect psychiatric risk loci.

evolutionary biology↗

bioRxiv2019

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

To provide novel insights into the biology of opioid dependence (OD) and opioid use (i.e., exposure, OE), we completed a genome-wide analysis comparing up to 4,503 OD cases, 4,173 opioid-exposed controls, and 32,500 opioid-unexposed controls. Among the variants identified, rs9291211 was associated with OE (a comparison of exposed vs. unexposed controls; z=-5.39, p=7.2x10-8). 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=1.68x10-8). With respect to the same OE phenotype in the gene-based analysis, we identified SDCCAG8 (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 (z=5.55, p=2.9x10-8) and a significant association with musculoskeletal disorders in the UK Biobank (p=4.88x10-7). A polygenic risk score (PRS) based on a GWAS of risk-tolerance (N=466,571) was positively associated with OD (OD cases vs. unexposed controls, p=8.1x10-5; OD cases vs. exposed controls, p=0.054) and OE (exposed controls vs. unexposed controls, p=3.6x10-5). A PRS based on a GWAS of neuroticism (N=390,278) was positively associated with OD (OD cases vs. unexposed controls, p=3.2x10-5; OD cases vs. exposed controls, p=0.002) but not with OE (p=0.671). Our analyses highlight the difference between dependence and exposure and the importance of considering the definition of controls (exposed vs. unexposed) in studies of addiction.

genetics↗

bioRxiv2019

Genomic Characterization of Posttraumatic Stress Disorder in a Large US Military Veteran Sample

Individuals vary in their liability to develop Posttraumatic Stress Disorder (PTSD), the symptoms of which are highly heterogeneous, following exposure to life-threatening trauma. Understanding genetic factors that contribute to the biology of PTSD is critical for refining diagnosis and developing new treatments. Using genetic data from more than 250,000 participants in the Million Veteran Program, genomewide association analyses were conducted using a validated electronic health record-based algorithmically-defined PTSD diagnosis phenotype (48,221 cases and 217,223 controls), and PTSD quantitative symptom phenotypes (212,007 individuals). We identified several genome-wide significant loci in the case-control analyses, and numerous such loci in the quantitative trait analyses, including some (e.g., MAD1L1; TCF4; CRHR1) that were associated with multiple symptom sub-domains and total symptom score, and others that were more specific to certain symptom sub-domains (e.g., CAMKV to re-experiencing; SOX6 to hyperarousal). Genetic correlations between all pairs of symptom sub-domains and their total were very high (rg 0.93 - 0.98) supporting validity of the PTSD diagnostic construct. We also demonstrate strong shared heritability with a range of traits, show that heritability persists when conditioned on other major psychiatric disorders, present independent replication results, provide support for one of the implicated genes in postmortem brain of individuals with PTSD, and use this information to identify potential drug repositioning candidates. These results point to the utility of genetics to inform and validate the biological coherence of the PTSD syndrome despite considerable heterogeneity at the symptom level, and to provide new directions for treatment development.

genetics↗

bioRxiv2019

Meta-analysis of problematic alcohol use in 435,563 individuals identifies 29 risk variants and yields insights into biology, pleiotropy and causality

Problematic alcohol use (PAU) is a leading cause of death and disability worldwide. Although genome-wide association studies (GWASs) have identified PAU risk genes, the genetic architecture of this trait is not fully understood. We conducted a proxy-phenotype meta-analysis of PAU combining alcohol use disorder and problematic drinking in 435,563 European-ancestry individuals. We identified 29 independent risk variants, 19 of them novel. PAU was genetically correlated with 138 phenotypes, including substance use and psychiatric traits. Phenome-wide polygenic risk score analysis in an independent biobank sample (BioVU, n=67,589) confirmed the genetic correlations between PAU and substance use and psychiatric disorders. Genetic heritability of PAU was enriched in brain and in genomic conserved and regulatory regions. Mendelian randomization suggested causal effects on liability to PAU of substance use, psychiatric status, risk-taking behavior, and cognitive performance. In summary, this large PAU meta-analysis identified novel risk loci and revealed genetic relationships with numerous other outcomes.

genetics↗

bioRxiv2019

Metabolome-Wide Mendelian Randomization Analysis of Emotional and Behavioral Responses to Traumatic Stress

Trauma exposure is an important risk factor for several psychiatric disorders; however, the mechanisms that underlie emotional and behavioral responses to traumatic stress are unclear. To understand these mechanisms, this study investigated the genetic overlap and causal relationship between blood metabolites and traits related to trauma response using genome-wide data. Five traits related to trauma response "in the past month" ascertained in the UK Biobank (52 816<N<117 900 individuals) were considered: i) "Avoided activities or situations because of previous stressful experience" (Avoidance); ii) "Felt distant from other people" (Distant); iii) "Felt irritable or had angry outbursts" (Irritable); iv) "Felt very upset when reminded of stressful experience" (Upset); v) "Repeated disturbing thoughts of stressful experience" (Repeated Thoughts). These were investigated with respect to 52 metabolites assessed using nuclear magnetic resonance metabolomics in a previous genome-wide association study (up to 24,925 individuals of European descent). Applying linkage disequilibrium score regression (LDSC), polygenic risk scoring (PRS), and Mendelian randomization (MR), we observed that 14 metabolites were significantly correlated with trauma response traits (p<0.05); PRS of 4 metabolites (citrate (CIT); glycoprotein acetyls (GP); concentration of large very-low-density lipoproteins (VLDL) particles (LVLDLP); total cholesterol in medium particles of VLDL (MVLDLC)) were associated with traits related to trauma response (false discovery rate Q<10%). These associations were partially due to causal relationships (CIT[->]Upset {beta}=-0.058, p=9.1x10-4; GP[->]Avoidance {beta}=0.008, p=0.003; LVLDLP[->]Distant {beta}=0.008, p=0.022; MVLDLC[->]Avoidance {beta}=0.019, p=3x10-4). No reverse associations were observed. In conclusion, the genetics of certain blood-metabolites are potentially implicated in the response to traumatic experience.

genetics↗

bioRxiv2019

Reproducible Risk Loci and Psychiatric Comorbidities in Anxiety: Results from ~200,000 Million Veteran Program Participants

We used GWAS in the Million Veteran Program sample (nearly 200,000 informative individuals) using a continuous trait for anxiety (GAD-2) to identify 5 genome-wide significant (GWS) signals for European Americans (EA) and 1 for African Americans. The strongest findings were on chromosome 3 (rs4603973, p=7.40x10-11) near the SATB1 locus, a global regulator of gene expression and on chromosome 6 (rs6557168, p=1.04x10-9) near ESR1 which encodes estrogen receptor . A locus identified on chromosome 7 near MADIL1 (p=1.62x10-8) has been previously identified in GWAS of bipolar disorder and of schizophrenia and may represent a risk factor for psychiatric disorders broadly. SNP-based heritability was estimated to be ~6% for GAD-2. We also GWASed for self-reported anxiety disorder diagnoses (N=224,330) and identified two GWS loci, one (rs35546597, MAF=0.42, p=1.88x10-8) near the AURKB locus, and the other (rsl0534613, MAF=0.41, p=4.92x10-8) near the IQCHE and MADIL1 locus identified in the GAD-2 analysis. We demonstrate reproducibility by replicating our top findings in the summary statistics from the Anxiety NeuroGenetics Study (ANGST) and a UK Biobank neuroticism GWAS. We also replicated top findings from a large UK Biobank preprint, demonstrating stability of GWAS findings in complex traits once sufficient power is attained. Finally, we found evidence of significant genetic overlap between anxiety and major depression using polygenic risk scores, but also found that the main anxiety signals are independent of those for MDD. This work presents novel insights into the neurobiological risk underpinning anxiety and related psychiatric disorders. SignificanceAnxiety disorders are common and often disabling. They are also frequently co-morbid with other mental disorders such as major depressive disorder (MDD); these disorders may share commonalities in their underlying genetic architecture. Using one of the largest homogenously phenotyped cohorts available, the Million Veteran Program sample, we investigated common variants associated with anxiety in genome-wide association studies (GWASes), using survey results from the GAD-2 anxiety scale (as a continuous trait, n=199,611), and self-reported anxiety disorder diagnosis (as a binary trait, n=224,330). This largest GWAS to date for anxiety and related traits identified numerous novel significant associations, several of which are replicated in other datasets, and allows inference of underlying biology.

genetics↗

bioRxiv2019

Genome-wide Association Study of Alcohol Consumption and Use Disorder in Multiple Populations (N = 274,424)

Although alcohol consumption level and alcohol use disorder (AUD) diagnosis are both moderately heritable, their genetic risks and overlap are not well understood. We conducted genome-wide association studies of these traits using longitudinal Alcohol Use Disorder Identification Test-Consumption (AUDIT-C) scores (reflecting alcohol consumption) and AUD diagnoses from electronic health records (EHRs) in a single, large multi-ancestry Million Veteran Program sample. Meta-analysis across population groups (N = 274,424) identified 18 genome-wide significant loci, 5 of which were associated with both traits and 13 with either AUDIT-C (N = 8) or AUD (N = 5). A significant genetic correlation between the traits reflects this overlap. However, downstream analyses revealed biologically meaningful points of divergence. Cell-type group partitioning heritability enrichment analyses indicated that central nervous system was the most significant cell type for AUDIT-C and the only significant cell type for AUD. Polygenic risk scores (PRS) for both traits were associated with alcohol-related disorders in two independent samples. Genetic correlations for 188 non-alcohol-related traits were significantly different for the two traits, as were the phenotypes associated with the traits polygenic risk scores. We conclude that EHR-derived, longitudinal, repeated measures of alcohol consumption level and AUD diagnosis can facilitate genetic discovery and help to elucidate the relationship between drinking level and AUD risk. Finally, although heavy drinking is a key risk factor for AUD, it is not a sufficient cause of the disorder.

genetics↗

bioRxiv2018

Economic status mediates the relationship between educational attainment and posttraumatic stress disorder: a multivariable Mendelian randomization study

ObjectivesTo investigate the genetic overlap and causal relationship between posttraumatic stress disorder (PTSD) and traits related to educational attainment.\n\nDesignGenetic correlation, polygenic risk scoring, and causal inference via multivariable Mendelian randomization (MR).\n\nSettingPsychiatric Genomics Consortium for PTSD, UK Biobank, 23andMe, and Social Science Genetic Association Consortium.\n\nParticipants23,185 PTSD cases and 151,309 controls; up to 1,131,881 individuals assessed for educational attainment and related traits.\n\nMain outcome measuresGenetic correlation obtained from linkage disequilibrium score regression, phenotypic variance explained by polygenic risk scores, and casual effects (beta values) estimated with MR\n\nResultsPTSD showed strong negative genetic correlations with educational attainment (EdAtt; rg=-0.26, p=4.6x10-8). PRS based on genome-wide significant variants associated with EdAtt significantly predicted PTSD (p=6.16x10-4), but PRS based on variants associated with PTSD did not predict EdAtt (p>0.05). MR analysis indicated that EdAtt has negative causal effects on PTSD (beta=-0.23, p=0.004). Investigating potential mediators of the EdAtt-PTSD relationship, we observed that propensity for trauma exposure and risk-taking behaviors are risk factors for PTSD independently from EdAtt (beta = 0.36, p = 2.57x10-5 and beta = 0.76, p = 6.75x10-4, respectively), while income fully mediates the causal effect of EdAtt on PSTD (MR: Income - beta = -0.18, p =0.001; EdAtt - beta =-0.23, p=0.004; multivariable MR: Income - beta = -0.32, p = 0.017; EdAtt - beta = -0.04, p = 0.786).\n\nConclusionsWe report novel findings based on large-scale datasets regarding the relationship between educational attainment and PTSD, supporting the role of economic status as the key mediator in the causal relationship observed.\n\nWhat is already known on this topicThere is a well-established negative association of educational attainment and other traits related to cognitive ability with posttraumatic stress disorders (PTSD). However, the findings of these previous studies support various possible causal explanations: 1) individuals with high educational attainment are more resilient with respect to developing PTSD, 2) PTSD negatively impacts cognitive ability, or 3) PTSD and educational attainment share some underlying determinants, including relevant molecular mechanisms.\n\nA key obstacle to disentangling the complex association between educational attainment and PTSD is reverse causation, i.e. the situation in which the outcome precedes and causes the exposure instead of the other way around.\n\nWhat this study addsWe conducted a causal-inference investigation based on large-scale information from the investigation of more than one million individuals. Our main assumption is that genetic information can strongly minimize the bias of reverse causation, because genetic variants are determined at conception and do not change throughout life.\n\nOur findings indicate 1) the effect of traits related to educational attainment on PTSD, 2) no reverse effect of PTSD on educational attainment, and 3) economic status mediates the relationship between educational attainment and PTSD, independently from the brain mechanisms related to educational attainment.

genetics↗

bioRxiv2018

DRD2 and FOXP2 are implicated in the associations between computerized device use and psychiatric disorders

1.The societal health effects of ubiquitous computerized device use (CDU) is mostly unknown. Epidemiological evidence supports associations between CDU and psychiatric traits, but the underlying biological mechanisms are unclear. We investigated genetic overlaps, causal relationships, and molecular pathways shared between these traits using genome-wide data regarding CDU (UK Biobank; up to N=361,194 individuals) and Psychiatric Genomics Consortium phenotypes (14,477<N<150,064). The strongest genetic correlations were between \"weekly usage of mobile phone in last 3 months\" (PhoneUse) vs. attention deficit hyperactivity disorder (ADHD) (rg=0.425, p=4.59x10-11) and \"plays computer games\" (CompGaming) vs. schizophrenia (SCZ) (rg=-0.271, p=7.16x10-26). Latent causal variable analysis did not support causal relationships between these traits, but the observed genetic overlap was related to shared molecular pathways, including: dopamine transport (Gene Ontology:0015872, pSCZvsCompGaming=2.74x10-10) and DRD2 association (pSCZ=7.94x10-8; pCompGaming=3.98x10-25), and FOXP2 association (pADHD=9.32x10-7; pPhoneUse=9.00x10-11). Our results support epidemiological observations with genetic data, and uncover biological mechanisms underlying psychiatric disorders contribution to CDUs.

genomics↗

bioRxiv2018

Evidence of causal effect of major depression on alcohol dependence: Findings from the Psychiatric Genomics Consortium

BackgroundDespite 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.\n\nMethodsThis study was conducted using genome-wide data from the Psychiatric Genomics Consortium (MD: 135,458 cases and 344,901 controls; AD: 10,206 cases and 28,480 controls) and UK Biobank (AC-Frequency: from \"daily or almost daily\" to \"never\", 438,308 individuals; AC-Quantity: total units of alcohol per week, 307,098 individuals). Linkage disequilibrium score regression and Mendelian Randomization (MR) analyses were applied to investigate shared genetic mechanisms (horizontal pleiotropy) and causal relationships (mediated pleiotropy) among these traits.\n\nOutcomesPositive genetic correlation was observed between MD and AD (rgMD-AD=+0.47, P=6.6x10-10). AC-Quantity showed positive genetic correlation with both AD (rgAD-AC-Quantity=+0.75, P=1.8x10-14) and MD (rgMD-AC-Quantity=+0.14, P=2.9x10-7), while there was negative correlation of AC-Frequency with MD (rgMD-AC-Frequency=-0.17, P=1.5x10-10) and a non-significant result with AD. MR analyses confirmed the presence of pleiotropy among these traits. However, the MD-AD results reflect a mediated-pleiotropy mechanism (i.e., causal relationship) with a causal role of MD on AD (beta=0.28, P=1.29x10-6) that does not appear to be biased by confounding such as horizontal pleiotropy. No evidence of reverse causation was observed as the AD genetic instrument did not show a causal effect on MD.\n\nInterpretationResults support a causal role for MD on AD based on genetic datasets including thousands of individuals. Understanding mechanisms underlying MD-AD comorbidity not only addresses important public health concerns but also has the potential to facilitate prevention and intervention efforts.\n\nFundingNational Institute of Mental Health and National Institute on Drug Abuse.\n\nPutting data into contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed up to August 24, 2018, for research studies that investigated causality among alcohol-and depression related phenotypes using Mendelian randomization approaches. We used the search terms \"alcohol\" AND \"depression\" AND \"Mendelian Randomization\". No restrictions were applied to language, date, or article type. Ten articles were retrieved, but only two were focused on alcohol consumption and depression-related traits. The studies were based on genetic variants in alcohol dehydrogenase (ADH) genes only, did not find evidence for a causal effect of alcohol consumption on depression phenotypes, with one study finding a causal effect of alcohol consumption on alcoholism. Both studies noted that future studies are needed with increased sample sizes and clinically derived phenotypes. To our knowledge, no previous study has applied two-sample Mendelian randomization to investigate causal relationships between alcohol dependence and major depression.\n\nTwin studies show genetic factors influence susceptibility to MD, AD, and alcohol consumption. Differently from observational approaches where several studies have investigated the relationship between alcohol-and depression-related phenotypes, very limited use of molecular genetic data has been applied to investigate this issue. Additionally, the use of genetic information has been shown to be less biased by confounders and reverse causation than observation data. However, genetic approaches, like Mendelian randomization, require large sample sizes to be informative.\n\nAdded value of this studyIn this study, we used genome-wide data from the Psychiatric Genomic Consortium and UK Biobank, which include information regarding hundred thousands of individuals, to test the presence of shared genetic mechanisms and causal relationships among major depression, alcohol dependence, and alcohol consumption. The results support a causal influence of MD on AD, while alcohol consumption showed shared genetic mechanisms with respect to both major depression and alcohol dependence.\n\nImplications of all the available evidenceGiven the significant morbidity and mortality associated with MD, AD, and the comorbid condition, understanding mechanisms underlying these associations not only address important public health concerns but also has the potential to facilitate prevention and intervention efforts.

genetics↗