Bivariate association analysis of longitudinal phenotypes in families.

Statistical genetic methods incorporating temporal variation allow for greater understanding of genetic architecture and consistency of biological variation influencing development of complex diseases. This study proposes a bivariate association method jointly testing association of two quantitative phenotypic measures from different time points. Measured genotype association was analyzed for single-nucleotide polymorphisms (SNPs) for systolic blood pressure (SBP) from the first and third visits using 200 simulated Genetic Analysis Workshop 18 (GAW18) replicates. Bivariate association, in which the effect of an SNP on the mean trait values of the two phenotypes is constrained to be equal for both measures and is included as a covariate in the analysis, was compared with a bivariate analysis in which the effect of an SNP was estimated separately for the two measures and univariate association analyses in 9 SNPs that explained greater than 0.001% SBP variance over all 200 GAW18 replicates.The SNP 3_48040283 was significantly associated with SBP in all 200 replicates with the constrained bivariate method providing increased signal over the unconstrained bivariate method. This method improved signal in all 9 SNPs with simulated effects on SBP for nominal significance (p-value <0.05). However, this appears to be determined by the effect size of the SNP on the phenotype. This bivariate association method applied to longitudinal data improves genetic signal for quantitative traits when the effect size of the variant is moderate to large.

An ADH1B variant and peer drinking in progression to adolescent drinking milestones: evidence of a gene-by-environment interaction.

BACKGROUND: Adolescent drinking is an important public health concern, one that is influenced by both genetic and environmental factors. The functional variant rs1229984 in alcohol dehydrogenase 1B (ADH1B) has been associated at a genome-wide level with alcohol use disorders in diverse adult populations. However, few data are available regarding whether this variant influences early drinking behaviors and whether social context moderates this effect. This study examines the interplay between rs1229984 and peer drinking in the development of adolescent drinking milestones. METHODS: One thousand five hundred and fifty European and African American individuals who had a full drink of alcohol before age 18 were selected from a longitudinal study of youth as part of the Collaborative Study on the Genetics of Alcoholism (COGA). Cox proportional hazards regression, with G × E product terms in the final models, was used to study 2 primary outcomes during adolescence: age of first intoxication and age of first DSM-5 alcohol use disorder symptom. RESULTS: The minor A allele of rs1229984 was associated with a protective effect for first intoxication (HR = 0.56, 95% CI 0.41 to 0.76) and first DSM-5 symptom (HR = 0.45, 95% CI 0.26 to 0.77) in the final models. Reporting that most or all best friends drink was associated with a hazardous effect for first intoxication (HR = 1.81, 95% CI 1.62 to 2.01) and first DSM-5 symptom (HR = 2.17, 95% 1.88 to 2.50) in the final models. Furthermore, there was a significant G × E interaction for first intoxication (p = 0.002) and first DSM-5 symptom (p = 0.01). Among individuals reporting none or few best friends drinking, the ADH1B variant had a protective effect for adolescent drinking milestones, but for those reporting most or all best friends drinking, this effect was greatly reduced. CONCLUSIONS: Our results suggest that the risk factor of best friends drinking attenuates the protective effect of a well-established ADH1B variant for 2 adolescent drinking behaviors. These findings illustrate the interplay between genetic and environmental factors in the development of drinking milestones during adolescence.

Association of NFKB1, which encodes a subunit of the transcription factor NF-kappaB, with alcohol dependence.

A broad region on chromosome 4q has been linked to alcohol dependence (alcoholism). We hypothesized that such broad linkage regions represent the combined action of multiple genes. Seeking to identify genes within that region that are associated with alcoholism, we have tested the association of NFKB1, located at 4q24, with alcoholism. NFKB1 encodes a 105 kDa transcription inhibitor that is cleaved to the 50 kDa DNA-binding subunit of the ubiquitous transcription factor NF-kappaB. NF-kappaB regulates many genes relevant to brain function, and its actions can be potentiated by ethanol; thus, NFKB1 is an excellent candidate gene for alcoholism. Nineteen SNPs in and near NFKB1 were analyzed in a sample of 219 multiplex alcoholic families of European American descent. Family-based association analyses detected significant evidence of association with eight SNPs and marginal evidence for five more. The association was driven by the affected individuals with earlier onset of alcoholism (55% of the sample with onset < or =21 years). Further analysis of the age of onset as a quantitative variable provided evidence for the association of 12 SNPs in this gene. Thus, variations in NFKB1 appear to affect the risk for alcoholism, particularly contributing to an earlier onset of the disease.

Assessment of sex-specific genetic and environmental effects on bone mineral density.

Although it is widely accepted that genes contribute significantly to the variation in bone mineral density (BMD), the nature of the genetic contribution is poorly defined. There are large gender differences in BMD, although whether sex-specific genetic effects influencing variation in BMD contribute to these differences is not known. To address this issue, we studied 929 subjects from large families participating in the Amish Family Osteoporosis Study. Bone mineral density was measured at the hip and spine by dual energy X-ray absorptiometry (DXA). We used variance decomposition procedures to partition variation in BMD into genetic and environmental effects common to both sexes and to men and women separately. After accounting for covariate effects, the heritability of BMD ranged from 0.63 to 0.72 in men and 0.80 to 0.87 in women. The residual environmental variance in BMD at the spine, but not hip, was significantly higher in men than in women (P < 0.05), reflecting a greater variance in BMD due to unexplained non-genetic factors in men. In contrast, there were no significant differences between men and women in the magnitude of the genetic variance in BMD, nor did the genetic correlation in BMD between men and women differ significantly from one. Overall, these analyses do not provide evidence for sex-specific genetic effects, suggesting that many of the genes influencing variation in BMD should be detectable in both men and women.