Some of the genes identifiedthrough this approach have been replicated across a number of studies and appear tobe robust genetic findings. Alcohol is widely consumed; however, excessive use creates serious physical, psychological and social problems and contributes to the pathogenesis of many diseases. Alcohol use disorders (that is, alcohol dependence and alcohol abuse) are maladaptive patterns of excessive drinking that lead to serious problems. Abundant evidence indicates that https://ecosoberhouse.com/ alcohol dependence (alcoholism) is a complex genetic disease, with variations in a large number of genes affecting a person’s risk of alcoholism. Some of these genes have been identified, including two genes involved in the metabolism of alcohol (ADH1B and ALDH2) that have the strongest known affects on the risk of alcoholism. Studies continue to reveal other genes in which variants affect the risk of alcoholism or related traits, including GABRA2, CHRM2, KCNJ6 and AUTS2.

3. Assortative mating, trigenerational analyses, and Mendelian randomization

Most current knowledge derives from studies of European-ancestry populations, and large studies of carefully phenotyped subjects from different populations are needed to understand the genetic contributions to alcohol consumption and alcohol use disorders. Parallel to the emphasis on increasing sample sizes to drive gene discovery is the growing recognition of the value of a sample like COGA with its family‐based design, deep phenotyping, longitudinal framework, multi‐modal data, wide age range, and ancestral diversity (see, Figure 2 for summary of key contributions enabled by COGA). Simply put, the family‐based COGA data are well‐suited to answer scientific questions that are not possible even in very large samples of unrelated individuals. Advances in our understanding of the genetic etiology of AUD will continue to depend on more detailed, family‐based designs in data‐rich samples like COGA, as well as large‐scale, collaborative meta‐analyses that incorporate summary data from COGA alongside many other cohorts.

Genetic correlations

• For example, in a whole-genome sequencing study of height, the SNP heritability of height was estimated to be 0.68 (s.e. 0.1), which is close to the pedigree estimates of 0.7–0.8 (ref. 48).
• H.Z., R.L.K., J.D.D., H.X., S.T., K.Y., P.A.L., L.F., L.W., A.S.H., J.J., H.L., T.T.M., J.X., K.J.A.J., E.C.J. and T.T.N. performed the analyses.
• If siblings who are alcoholic share more alleles at a marker than would be expected based on chance, this suggests that genes within the chromosomal region containing the marker contribute to the risk of alcoholism.
• The GI tract is exposed to very high levels of alcohol as it passes throughthe mouth, esophagus, stomach and intestinal tract, and most ethanol passes throughthe liver before entering the circulation.
• A GWAS of AUD that included AUDIT-C as a covariate identified five GWS loci in EAs and one in AAs (Supplementary Data 8).

1The term “phenotype” refers to any observable characteristic or behavior of an individual. †Note that the official names of several ADH genes have been changed, and theliterature has been confused by some groups using non-standard names for some ofthe genes29.

Associated Data

Thus, thegenes and SNPs found through GWAS have had little overlap with previous findingsbased on candidate genes/pathways and linkage analyses. Studies in humans have begun to elucidate the genetic underpinnings of the risk for alcoholism. Here we briefly review strategies for identifying individual genes in which variations affect the risk for alcoholism and related phenotypes, in the context of one large study that has successfully identified such genes.

• Recent efforts in the search for AUD susceptibility genes will be reviewed in this article.
• In the study of complex disorders, it has become apparent that quitelarge sample sizes are critical if robust association results are to beidentified which replicate across studies.
• The genetics of alcohol use disorder isn’t just about the genes we inherit but also about how they interact with our brain’s structures and functions.
• We also conducted PheWAS in Yale–Penn, a deeply phenotyped cohort with comprehensive psychiatric assessments (SUDs and psychiatric disorders) and assessments for physical and psychosocial traits28.
• The single-nucleotide polymorphism (SNP) heritability of alcohol dependence in a family-based, European-American (EA) sample was 16%10 and 22% in an unrelated African-American (AA) sample11.

Supplementary Data 30

People with a genetic predisposition to alcoholism often start drinking due to environmental stressors. Hereditary predisposition to AUD is one of the risk factors identified by these results. It’s essential to note that while fraternal twins have distinct genetic profiles, identical twins share the exact genome.

The study also included a large sample of control families that were randomly selected from the community. For the analyses, the researchers chose a split-sample design—two groups of subjects (i.e., an initial sample and a replication sample) were analyzed independently; this approach allows investigators to examine the reproducibility of the initial study findings. The purpose of the Collaborative Study on the Genetics of Alcoholism (COGA) is to advance knowledge about the complex influences of gene and environment on development and progression of alcohol use disorder (AUD). From its inception, COGA has generated and utilized extensive arrays of genotypic and phenotypic data from families densely affected by AUD and from comparison families to identify genes and understand their role in susceptibility to (or protection from) developing AUD and related phenotypes.

Summary statistics for AUD/AD GWAS from five EAS cohorts (MVP EAS, Han Chinese–GSA, Thai METH–MEGA, Thai METH–GSA and Han Chinese–Cyto) were included in the cross-ancestry meta-analysis. Analyses of these five cohorts were previously published and the detailed QC can be found in ref. 26. If you or a loved one has a high risk for alcohol addiction, knowing the early warning signs of dependence helps.

Is AUD genetic?

This article does not contain any studies with human or animal subjects performed by the author. Published today in Nature Mental Health, the study was led by researchers at the Washington University in St. Louis, along with more than 150 coauthors from around the world. It was supported by the National Institute on Drug Abuse (NIDA), the National Institute on Alcohol Abuse and Alcoholism (NIAAA), the National Institute of Mental Health (NIMH), the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute on Aging.

• Research has illuminated that genetics is a significant factor in the risk of developing Alcohol Use Disorder (AUD), but it’s not the only one.
• This suggests that while a family history of alcoholism can increase susceptibility, it doesn’t dictate destiny.
• Furthermore, aggregating across multiple SUDs suggests that problematic and disordered substance use has a unique genetic architecture that, while shared across SUDs, does not overlap fully with nondependent substance use per se16.
• Today, studies have demonstrated that genes could predispose a person to alcohol dependence.
• AUD and AUDIT–P index aspects of excessive alcohol intake and higher risk of which correlate with genetic liability to psychiatric and psychosocial factors (for example, higher risk for major depressive disorder and lower educational attainment (EA)).

New NIH study reveals shared genetic markers underlying substance use disorders

The single-nucleotide polymorphism (SNP) heritability of alcohol dependence in a family-based, European-American (EA) sample was 16%10 and 22% in an unrelated African-American (AA) sample11. In the meta-analysis of data from the UK Biobank (UKBB) and 23andMe, the SNP heritability of the total AUDIT was estimated to be 12%, while for the AUDIT-C and AUDIT-P it was 11% and 9%, respectively). They may increase the overall risk by increasing drinking, orreduce risk by reducing drinking. Some alleles that reduce heavy drinking can,nevertheless, increase risk for disease in the subset of individuals who drinkheavily despite having them.

• Subsequent analyses that included the additional markers supported the initial findings (Foroud et al. 2000) but did not narrow the chromosomal regions in which genes influencing alcoholism susceptibility are likely to lie.
• Two of these genes are the dopamine D2 receptor gene (DRD2) and a serotonin transporter gene (HTT).
• We explored trait and disease associations for AUDIT-C-adjusted for AUD and AUD-adjusted for AUDIT-C, and found that the genetic correlations between the alcohol-related traits and other phenotypes did not differ substantially from the unadjusted ones (Supplementary Data 37, 38).
• HapMap data and other studies [52] reveal moderate long distance linkage disequilibrium across GABRA2 and the closely adjacent gene GABRG1 raising the possibility that the functional locus is in GABRG1.
• Here we briefly review strategies for identifying individual genes in which variations affect the risk for alcoholism and related phenotypes, in the context of one large study that has successfully identified such genes.
• A second approach that will likely benefit the alcohol researchcommunity will be greater examination of pathways or gene sets.
• As in EUR, AUD in AFR was genetically correlated with substance use traits including OUD, smoking trajectory (that identifies groups of individuals that follow a similar progression of smoking behavior), and maximum habitual alcohol intake.

Pathway and biological enrichment analyses

New genetic variants have been identified, refined endophenotypes have been characterized, and functional information has begun to emerge on known genetic variants that influence risk for and protection from AUD. Over the past few years numerous whole genome linkage studies have been performed in which the inheritance of phenotypes and genetic markers is followed in families [12,40]. Two influential linkage scans, one in a Southwestern American Indian tribe, a population isolate [41], and the other in the large, predominantly Caucasian Collaborative Study on the genetics of alcoholism (COGA) dataset [42] found evidence for linkage of AUD near the chromosome 4 GABAA receptor subunit gene cluster.