Genetic effects on DNA methylation and its potential relevance for obesity in Mexican Americans.

Several studies have identified effects of genetic variation on DNA methylation patterns and associated heritability, with research primarily focused on Caucasian individuals. In this paper, we examine the evidence for genetic effects on DNA methylation in a Mexican American cohort, a population burdened by a high prevalence of obesity. Using an Illumina-based platform and following stringent quality control procedures, we assessed a total of 395 CpG sites in peripheral blood samples obtained from 183 Mexican American individuals for evidence of heritability, proximal genetic regulation and association with age, sex and obesity measures (i.e. waist circumference and body mass index). We identified 16 CpG sites (~4%) that were significantly heritable after Bonferroni correction for multiple testing and 27 CpG sites (~6.9%) that showed evidence of genetic effects. Six CpG sites (~2%) were associated with age, primarily exhibiting positive relationships, including CpG sites in two genes that have been implicated in previous genome-wide methylation studies of age (FZD9 and MYOD1). In addition, we identified significant associations between three CpG sites (~1%) and sex, including DNA methylation in CASP6, a gene that may respond to estradiol treatment, and in HSD17B12, which encodes a sex steroid hormone. Although we did not identify any significant associations between DNA methylation and the obesity measures, several nominally significant results were observed in genes related to adipogenesis, obesity, energy homeostasis and glucose homeostasis (ARHGAP9, CDKN2A, FRZB, HOXA5, JAK3, MEST, NPY, PEG3 and SMARCB1). In conclusion, we were able to replicate several findings from previous studies in our Mexican American cohort, supporting an important role for genetic effects on DNA methylation. In addition, we found a significant influence of age and sex on DNA methylation, and report on trend-level, novel associations between DNA methylation and measures of obesity.

Integrating genomic analysis with the genetic basis of gene expression: preliminary evidence of the identification of causal genes for cardiovascular and metabolic traits related to nutrition in Mexicans.

Whole-transcriptome expression profiling provides novel phenotypes for analysis of complex traits. Gene expression measurements reflect quantitative variation in transcript-specific messenger RNA levels and represent phenotypes lying close to the action of genes. Understanding the genetic basis of gene expression will provide insight into the processes that connect genotype to clinically significant traits representing a central tenet of system biology. Synchronous in vivo expression profiles of lymphocytes, muscle, and subcutaneous fat were obtained from healthy Mexican men. Most genes were expressed at detectable levels in multiple tissues, and RNA levels were correlated between tissue types. A subset of transcripts with high reliability of expression across tissues (estimated by intraclass correlation coefficients) was enriched for cis-regulated genes, suggesting that proximal sequence variants may influence expression similarly in different cellular environments. This integrative global gene expression profiling approach is proving extremely useful for identifying genes and pathways that contribute to complex clinical traits. Clearly, the coincidence of clinical trait quantitative trait loci and expression quantitative trait loci can help in the prioritization of positional candidate genes. Such data will be crucial for the formal integration of positional and transcriptomic information characterized as genetical genomics.

A linkage analysis of cigarette and alcohol consumption in an unselected Mexican American population.

The use of alcohol and tobacco is highly prevalent. Studying the rate of consumption in a non-selected population could contribute to the elucidation of pathways involved in addiction or to the development of prevention programs. The San Antonio Family Heart Study has approximately 1,400 members with longitudinal data and did not select the proband with regard to exposure status. The goal of this study was to perform genome-wide linkage analysis of the rate of alcohol and cigarette consumption in a "normal" population. We used SOLAR to perform variance-components based analysis of the transformed maximal rate of consumption. Despite estimated heritabilities of 0.52 (P < 0.001) for cigarette and 0.39 (P < 0.001) for alcohol consumption, univariate linkage analyses produced only suggestive LOD scores, however the second suggestive linkage peak for the alcohol phenotype was present at 148 cM on chromosome 10, in the exact vicinity of the peak for the cigarette phenotype. In a bivariate analyses, the environmental correlation between alcohol and cigarette consumption was not significantly different from zero (rho(e) = -0.15, P = 0.18) and the overall genetic correlation was not different from zero (rho(g) = 0.16, P = 0.34). The results from the bivariate linkage analysis found a maximum LOD score of 3.82 (genome-wide P = 0.0054) at 151 cM on chromosome 10, at the location of the overlapping peaks from the univariate analyses.