Heritability of Alcohol Use Disorder: Evidence from Twin Studies and Genome-Wide Association Studies

Genetic Inheritance ◽

Genome Wide ◽

Shared Environments

‘What are the contributions of environments and genes to intelligence differences?’ asks whether genetic inheritance and the environments people experience affect intelligence differences. Researchers use two main resources to answer this question: twins and samples of DNA. Studies of identical and non-identical twins are used to show the contributions of genes, shared environment, and non-shared environment to people’s differences in traits. Twin studies tell us that by adulthood, about two-thirds of intelligence differences are caused by how people vary in their genetic inheritance, and that both shared and non-shared environments make significant contributions to intelligence differences. The introduction of genome-wide association studies in 2011 has provided a new method of estimating the heritability of intelligence.

Genome-wide Meta-analysis of Alcohol Use Disorder in East Asians

10.1101/2021.09.17.21263732 ◽

2021 ◽

Author(s):

Hang Zhou ◽

Rasmon Kalayasiri ◽

Yan Sun ◽

Yaira Z. Nuñez ◽

Hong-Wen Deng ◽

...

Keyword(s):

Alcohol Use ◽

Alcohol Use Disorder ◽

Association Studies ◽

Meta Analysis ◽

East Asian ◽

Han Chinese ◽

Polygenic Risk Score ◽

East Asians ◽

AbstractBACKGROUNDAlcohol use disorder (AUD) is a leading cause of death and disability worldwide. Genome-wide association studies (GWAS) have identified ∼30 AUD risk genes in European populations, but many fewer in East Asians.METHODSWe conducted GWAS and genome-wide meta-analysis of AUD in 13,551 subjects with East Asian ancestry, using published summary data and newly genotyped data from four cohorts: 1) electronic health record (EHR)-diagnosed AUD in the Million Veteran Program (MVP)sample; 2) DSM-IV diagnosed alcohol dependence (AD) in a Han Chinese-GSA (array) cohort;3) AD in a Han Chinese-Cyto (array) cohort; and 4) two AD datasets in a Thai cohort. The MVP and Thai samples included newly genotyped subjects from ongoing recruitment. In total, 2,254 cases and 11,297 controls were analyzed. An AUD polygenic risk score was analyzed in an independent sample with 4,464 East Asians (Kaiser Permanente data from dbGaP). Phenotypes from survey data and ICD-9-CM diagnoses were tested for association with the AUD PRS.RESULTSTwo risk loci were detected: the well-known functional variant rs1229984 in ADH1B and rs3782886 in BRAP (near the ALDH2 gene locus) are the lead variants. AUD PRS was significantly associated with days per week of alcohol consumption (beta = 0.43, se = 0.067, p = 2.47×10−10) and nominally associated with pack years of smoking (beta = 0.09, se = 0.05, p = 4.52×10−2) and ever vs. never smoking (beta = 0.06, se = 0.02, p = 1.14×10−2).CONCLUSIONSThis is the largest GWAS of AUD in East Asians to date. Building on previous findings, we were able to analyze pleiotropy, but did not identify any new risk regions, underscoring the importance of recruiting additional East Asian subjects for alcohol GWAS.

Evidence of shared genetic influences underlying schizophrenia and alcohol use disorder, but not alcohol consumption

10.1101/2020.10.27.20220186 ◽

2020 ◽

Author(s):

Emma C. Johnson ◽

Manav Kapoor ◽

Alexander S. Hatoum ◽

Hang Zhou ◽

Renato Polimanti ◽

...

Keyword(s):

Alcohol Consumption ◽

Alcohol Use ◽

Genetic Variants ◽

Alcohol Use Disorder ◽

Association Studies ◽

Genetic Correlations ◽

Genetic Covariance ◽

Genome Wide ◽

Brain Tissues

AbstractBackgroundAlcohol use disorder (AUD) and schizophrenia (SCZ) frequently co-occur, and recent genome-wide association studies (GWAS) have identified significant genetic correlations between them. In parallel, mounting evidence from GWAS suggests that alcohol consumption is only weakly genetically correlated with SCZ, but this has not yet been systematically investigated.MethodsWe used the largest published GWAS for AUD (total cases = 77,822) and SCZ (total cases = 46,827) to systematically identify genetic variants that influence both disorders (in either the same or opposite direction of effect) as well as disorder-specific loci, and contrast our findings with GWAS data for drinks per week (DPW; N = 537,349) as a measure of alcohol consumption.ResultsWe identified 55 independent genome-wide significant SNPs with the same direction of effect on AUD and SCZ, 9 with robust opposite effects, and 99 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). The genetic correlation between DPW and SCZ (rg = 0.102, SE = 0.022) was significantly lower than that for AUD and SCZ (rg = 0.392, SE = 0.029; p-value of the difference = 9.3e-18), and the genetic covariance between DPW and SCZ was not enriched for any meaningful tissue-specific categories.ConclusionsOur findings provide a detailed view of genetic loci that influence risk of both AUD and SCZ, suggest that biological commonalities underlying genetic variants with an effect on both disorders are manifested in brain tissues, and provide further evidence that SCZ shares meaningful genetic overlap with AUD and not merely alcohol consumption.

Twin studies, genome-wide association studies and myopia genetics

Annals of Eye Science ◽

10.21037/aes.2017.12.01 ◽

2018 ◽

Vol 2 ◽

pp. 69-69 ◽

Cited By ~ 4

Author(s):

Katie M. Williams ◽

Pirro Hysi ◽

Christopher J. Hammond

Keyword(s):

Association Studies ◽

Twin Studies ◽

Genome Wide Association ◽

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

10.1101/527929 ◽

2019 ◽

Author(s):

Henry R. Kranzler ◽

Hang Zhou ◽

Rachel L. Kember ◽

Rachel Vickers Smith ◽

Amy C. Justice ◽

...

Keyword(s):

Alcohol Consumption ◽

Alcohol Use ◽

Alcohol Use Disorder ◽

Genome Wide Association ◽

Risk Scores ◽

Cell Type ◽

Polygenic Risk ◽

Consumption Level ◽

SummaryAlthough 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.

Genome-Wide Association Study Reveals First Locus for Anorexia Nervosa and Metabolic Correlations

10.1101/088815 ◽

2016 ◽

Cited By ~ 4

Author(s):

E. L. Duncan ◽

L. M. Thornton ◽

A. Hinney ◽

M. J. Daly ◽

P. F. Sullivan ◽

...

Keyword(s):

Anorexia Nervosa ◽

Genome Wide Association Study ◽

Association Studies ◽

Genetic Correlations ◽

Twin Studies ◽

Hdl Cholesterol ◽

Genome Wide Association ◽

High Morbidity ◽

AbstractAnorexia nervosa (AN) is a serious eating disorder characterized by restriction of energy intake relative to requirements, resulting in abnormally low body weight. It has a lifetime prevalence of approximately 1%, disproportionately affects females1,2, and has no well replicated evidence of effective pharmacological or psychological treatments despite high morbidity and mortality2. Twin studies support a genetic basis for the observed aggregation of AN in families3, with heritability estimates of 48%-74%4. Although initial genome-wide association studies (GWASs) were underpowered5,6, evidence suggested that signals for AN would be detected with increased power5. We present a GWAS of 3,495 AN cases and 10,982 controls with one genome-wide significant locus (index variant rs4622308, p=4.3x10−9) in a region (chr12:56,372,585-56,482,185) which includes six genes. The SNP-chip heritability of AN from these data is 0.20 (SE=0.02), suggesting that a substantial fraction of the twin-based heritability stems from common genetic variation. Using these GWAS results, we also find significant positive genetic correlations with schizophrenia, neuroticism, educational attainment, and HDL cholesterol, and significant negative genetic correlations with body mass, insulin, glucose, and lipid phenotypes. Our results support the reconceptualization of AN as a disorder with both psychiatric and metabolic components.

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

Psychological Medicine ◽

10.1017/s003329172100266x ◽

2021 ◽

pp. 1-9

Author(s):

Emma C. Johnson ◽

Manav Kapoor ◽

Alexander S. Hatoum ◽

Hang Zhou ◽

Renato Polimanti ◽

...

Keyword(s):

Alcohol Use ◽

Alcohol Use Disorder ◽

Large Scale ◽

Association Studies ◽

Genetic Correlations ◽

Nucleotide Polymorphisms ◽

Genetic Covariance ◽

Specific Effects ◽

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.

Dimensional phenotypes in psychiatric genetics: lessons from genome-wide association studies of alcohol use phenotypes

Complex Psychiatry ◽

10.1159/000518863 ◽

2021 ◽

Author(s):

Travis T. Mallard ◽

Sandra Sanchez-Roige

Keyword(s):

Alcohol Use ◽

Association Studies ◽

Genome Wide Association ◽

Psychiatric Genetics ◽

Germline burden of rare damaging variants negatively affects human healthspan and lifespan

eLife ◽

10.7554/elife.53449 ◽

2020 ◽

Vol 9 ◽

Cited By ~ 3

Author(s):

Anastasia V Shindyapina ◽

Aleksandr A Zenin ◽

Andrei E Tarkhov ◽

Didac Santesmasses ◽

Peter O Fedichev ◽

...

Keyword(s):

Genetic Variants ◽

Aging Process ◽

Rare Variants ◽

Association Studies ◽

Twin Studies ◽

Genome Wide Association ◽

Mortality And Morbidity ◽

Human Lifespan ◽

Heritability of human lifespan is 23–33% as evident from twin studies. Genome-wide association studies explored this question by linking particular alleles to lifespan traits. However, genetic variants identified so far can explain only a small fraction of lifespan heritability in humans. Here, we report that the burden of rarest protein-truncating variants (PTVs) in two large cohorts is negatively associated with human healthspan and lifespan, accounting for 0.4 and 1.3 years of their variability, respectively. In addition, longer-living individuals possess both fewer rarest PTVs and less damaging PTVs. We further estimated that somatic accumulation of PTVs accounts for only a small fraction of mortality and morbidity acceleration and hence is unlikely to be causal in aging. We conclude that rare damaging mutations, both inherited and accumulated throughout life, contribute to the aging process, and that burden of ultra-rare variants in combination with common alleles better explain apparent heritability of human lifespan.

Genetics and pain in childhood

Oxford Textbook of Pediatric Pain ◽

10.1093/med/9780198818762.003.0009 ◽

2021 ◽

pp. 79-86

Author(s):

Jeffrey S. Mogil

Keyword(s):

Candidate Gene ◽

Association Studies ◽

Single Gene ◽

Gene Mutations ◽

Twin Studies ◽

Genome Wide Association ◽

Pediatric Pain ◽

Genome Wide ◽

Pediatric Populations

Genomic and other “omic” approaches are now routinely applied to the study of pain. Some of these investigations have utilized pediatric populations. This review describes what is currently known about the heritability of pain in children (from twin studies), genes relevant to pain in children (from single-gene mutations, candidate gene, and genome-wide association studies), and the application of newer techniques, such as epigenomics, to pediatric pain.