Dataset Information

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

ABSTRACT:

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.

SUBMITTER: Johnson EC

PROVIDER: S-EPMC8738774 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Publications

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

Johnson Emma C EC Kapoor Manav M Hatoum Alexander S AS Zhou Hang H Polimanti Renato R Wendt Frank R FR Walters Raymond K RK Lai Dongbing D Kember Rachel L RL Hartz Sarah S Meyers Jacquelyn L JL Peterson Roseann E RE Ripke Stephan S Bigdeli Tim B TB Fanous Ayman H AH Pato Carlos N CN Pato Michele T MT Goate Alison M AM Kranzler Henry R HR O'Donovan Michael C MC Walters James T R JTR Gelernter Joel J Edenberg Howard J HJ Agrawal Arpana A

Psychological medicine 20210707 4

<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>W ...[more]

PMID: 34231451

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Project description:BackgroundMedical conditions related to alcohol use disorders (AUD) represent a substantial public health concern. However, only a subset of individuals with AUD develop these conditions and the extent to which genetic and environmental factors that are shared with AUD, versus those distinct from it, contribute to this progression has not yet been determined.MethodsUsing data from Swedish national registries for a cohort born from 1932 to 1970 (N = 1,319,214, 48.9% women), we conducted twin-sibling biometric model fitting to examine the genetic and environmental sources of variance that contribute to the liability to alcohol-related medical conditions (AMC). Progression to AMC, determined using medical registry data, was contingent on an AUD registration, which was determined using medical and criminal registry data.ResultsWe identified AUD registrations in 3.2% of women and 9.2% of men. Among individuals with an AUD registration, 14.4% of women and 15.4% of men had an AMC registration. In the final models, we constrained the beta pathway from AUD to AMC and the genetic and unique environmental paths to be equal across sexes. The beta path was estimated at 0.59. AMC was modestly heritable in women (A = 0.32) and men (A = 0.30). The proportion of total heritability unique to AMC was 39.6% among women and 41.3% among men. A higher proportion of total environmental variance was unique to AMC: 76.7% for women and 77.2% for men. In a sensitivity analysis limited to liver-related AMC, we observed similar results, with a slightly lower beta path from AUD to AMC (0.46) and higher proportions of AMC-specific genetic (70.0% in women; 71.7% in men) and environmental (84.5% in both sexes) variance.ConclusionsA moderate-to-substantial proportion of genetic and environmental variance that contributes to AMC risk is not shared with AUD, underscoring the need for additional gene identification efforts for AMC. Furthermore, the prominent influence of environmental factors specific to AMC provides a promising area for the identification of prevention targets. We did not observe significant sex differences in the etiology of AMC, although follow-up is warranted in other well-powered studies.

Project description:We tested whether aspects of the childhood/adolescent home environment mediate genetic risk for alcohol problems within families across generations. Parental relationship discord and parental divorce were the focal environments examined. The sample included participants of European ancestry (N = 4806, 51% female) and African ancestry (N = 1960, 52% female) from the high-risk Collaborative Study on the Genetics of Alcoholism. Alcohol outcomes in the child generation included lifetime criterion counts for DSM-5 Alcohol Use Disorder (AUD), lifetime maximum drinks in 24 h, age at initiation of regular drinking, and age at first alcohol intoxication. Predictors in the parent generation included relationship discord, divorce, alcohol measures parallel to those in the child generation, and polygenic scores for alcohol problems. Parental polygenic scores were partitioned into alleles that were transmitted and non-transmitted to the child. The results from structural equation models were consistent with genetic nurture effects in European ancestry families. Exposure to parental relationship discord and parental divorce mediated, in part, the transmission of genetic risk for alcohol problems from parents to children to predict earlier ages regular drinking (βindirect = -0.018 [-0.026, -0.011]) and intoxication (βindirect = -0.015 [-0.023, -0.008]), greater lifetime maximum drinks (βindirect = 0.006 [0.002, 0.01]) and more lifetime AUD criteria (βindirect = 0.011 [0.006, 0.016]). In contrast, there was no evidence that parental alleles had indirect effects on offspring alcohol outcomes via parental relationship discord or divorce in the smaller number of families of African ancestry. In conclusion, parents transmit genetic risk for alcohol problems to their children not only directly, but also indirectly via genetically influenced aspects of the home environment. Further investigation of genetic nurture in non-European samples is needed.

Dataset Information

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

Background

Methods

Results

Conclusions

Publications

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

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