Excessive alcohol consumption is one of the leading causes of preventable death in the United States. Approximately 14% of those who use alcohol meet criteria during their lifetime for alcohol dependence, which is characterized by tolerance, withdrawal, inability to stop drinking, and continued drinking despite serious psychological or physiological problems. We explored genetic influences on alcohol dependence among 1,897 European-American and African-American subjects with alcohol dependence compared with 1,932 unrelated, alcohol-exposed, nondependent controls. Constitutional DNA of each subject was genotyped using the Illumina 1M beadchip. Fifteen SNPs yielded
P
< 10
−5
, but in two independent replication series, no SNP passed a replication threshold of
P
< 0.05. Candidate gene
GABRA2
, which encodes the GABA receptor α2 subunit, was evaluated independently. Five SNPs at
GABRA2
yielded nominal (uncorrected)
P
< 0.05, with odds ratios between 1.11 and 1.16. Further dissection of the alcoholism phenotype, to disentangle the influence of comorbid substance-use disorders, will be a next step in identifying genetic variants associated with alcohol dependence.
Using data from The Collaborative Study on the Genetics of Alcoholism, we compare direct interview diagnoses of alcohol dependence to those obtained by history from family members. Using a requirement of three or more positive implications by history, the specificity, sensitivity, and positive predictive values are @YO, 39%, and 45%, respectively.A logistic analysis found the gender of the relative and alcoholism in the informant to be significant, but not the gender of the informant.The partial odds ratio of a diagnosis at interview associated with a positive family history diagnosis was 13.6. The relationship between the informant and relative was significant, with negative reports from an offspring or mate more influential than a negative report from a parent or second-degree relative.We derived a recursive equation to combine a variable number of family history reports, wherein the probabilities associated with a single report are computed from the logistic analysis. This permits the use of family history information both as a proxy for an uninterviewed relative, as well as a second source of information to be used in the analysis of genetic family data.
A region along chromosome 7q was recently linked to components of the metabolic syndrome (MetS) in several genome-wide linkage studies. Within this region, the CD36 gene, which encodes a membrane receptor for long-chain fatty acids and lipoproteins, is a potentially important candidate. CD36 has been documented to play an important role in fatty acid metabolism in vivo and subsequently may be involved in the etiology of the MetS. The protein also impacts survival to malaria and the influence of natural selection has resulted in high CD36 genetic variability in populations of African descent. We evaluated 36 tag SNPs across CD36 in the HyperGen population sample of 2020 African-Americans for impact on the MetS and its quantitative traits. Five SNPs associated with increased odds for the MetS [P = 0.0027-0.03, odds ratio (OR) = 1.3-1.4]. Coding SNP, rs3211938, previously shown to influence malaria susceptibility, is documented to result in CD36 deficiency in a homozygous subject. This SNP conferred protection against the MetS (P = 0.0012, OR = 0.61, 95%CI: 0.46-0.82), increased high-density lipoprotein cholesterol, HDL-C (P = 0.00018) and decreased triglycerides (P = 0.0059). Fifteen additional SNPs associated with HDL-C (P = 0.0028-0.044). We conclude that CD36 variants may impact MetS pathophysiology and HDL metabolism, both predictors of the risk of heart disease and type 2 diabetes.
Unlike DSM-IV subtypes of ADHD, latent-class ADHD subtypes appear to be independently transmitted in families. These classes may be more appropriate targets for molecular genetic studies of ADHD.
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