Gene-alcohol interactions identify several novel blood pressure loci including a promising locus near SLC16A9

Alcohol consumption is a known risk factor for hypertension, with recent candidate studies implicating gene-alcohol interactions in blood pressure (BP) regulation. We used 6,882 (predominantly) Caucasian participants aged 20 to 80 years from the Framingham SHARe (SNP Health Association Resource) to perform a genome-wide analysis of SNP-alcohol interactions on BP traits. We used a two-step approach in the ABEL suite to examine genetic interactions with three alcohol measures [ounces of alcohol consumed per week, drinks consumed per week, and the number of days drinking alcohol per week] on four BP traits [systolic (SBP), diastolic (DBP), mean arterial (MAP), and pulse (PP) pressure]. In the first step, we fit a linear mixed model of each BP trait onto age, sex, BMI, and antihypertensive medication while accounting for the phenotypic correlation among relatives. In the second step, we conducted 1 degree-of-freedom (df) score tests of the SNP main effect, alcohol main effect, and SNP-alcohol interaction using the maximum likelihood estimates of the parameters from the first step. We then calculated the joint 2 df score test of the SNP main effect and SNP-alcohol interaction using MixABEL. The effect of SNP rs10826334 (near SLC16A9) on SBP was significantly modulated by both the number of alcoholic drinks and the ounces of alcohol consumed per week (p-values of 1.27E-08 and 3.92E-08, respectively). Each copy of the G-allele decreased SBP by 3.79 mmHg in those consuming 14 drinks per week versus a 0.461 mmHg decrease in non-drinkers. Index SNPs in 20 other loci exhibited suggestive (p-value≤1E-06) associations with BP traits by the 1 df interaction test or joint 2df test, including 3 rare variants, one low-frequency variant, and SNPs near/in genes ESRRG, FAM179A, CRIPT-SOCS5, KAT2B,ADCY2, GLI3, ZNF716, SLIT1, PDE3A, KERA-LUM, RNF219-AS1, CLEC3A , FBX015, and IGSF5. SNP -alcohol interactions may enhance discovery of novel variants with large effects that can be targete

Comparison of two methods for analysis of gene-environment interactions in longitudinal family data: The Framingham heart study

Gene–environment interaction (GEI) analysis can potentially enhance gene discovery for common complex traits. However, genome-wide interaction analysis is computationally intensive. Moreover, analysis of longitudinal data in families is much more challenging due to the two sources of correlations arising from longitudinal measurements and family relationships. GWIS of longitudinal family data can be a computational bottleneck. Therefore, we compared two methods for analysis of longitudinal family data: a methodologically sound but computationally demanding method using the Kronecker model (KRC) and a computationally more forgiving method using the hierarchical linear model (HLM). The KRC model uses a Kronecker product of an unstructured matrix for correlations among repeated measures (longitudinal) and a compound symmetry matrix for correlations within families at a given visit. The HLM uses an autoregressive covariance matrix for correlations among repeated measures and a random intercept for familial correlations. We compared the two methods using the longitudinal Framingham heart study (FHS) SHARe data. Specifically, we evaluated SNP–alcohol (amount of alcohol consumption) interaction effects on high density lipoprotein cholesterol (HDLC). Keeping the prohibitive computational burden of KRC in mind, we limited the analysis to chromosome 16, where preliminary cross-sectional analysis yielded some interesting results. Our first important finding was that the HLM provided very comparable results but was remarkably faster than the KRC, making HLM the method of choice. Our second finding was that longitudinal analysis provided smaller P-values, thus leading to more significant results, than cross-sectional analysis. This was particularly pronounced in identifying GEIs. We conclude that longitudinal analysis of GEIs is more powerful and that the HLM method is an optimal method of choice as compared to the computationally (prohibitively) intensive KRC method

Five Blood Pressure Loci Identified by an Updated Genome-Wide Linkage Scan: Meta-Analysis of the Family Blood Pressure Program

Background A preliminary genome-wide linkage analysis of blood pressure in the Family Blood Pressure Program (FBPP) was reported previously. We harnessed the power and ethnic diversity of the final pooled FBPP dataset to identify novel loci for blood pressure thereby enhancing localization of genes containing less common variants with large effects on blood pressure levels and hypertension. Methods We performed one overall and 4 race-specific meta-analyses of genome-wide blood pressure linkage scans using data on 4,226African-American, 2,154 Asian, 4,229 Caucasian, and 2,435 Mexican- American participants (total N = 13,044). Variance components models were fit to measured (raw) blood pressure levels and two types of antihypertensive medication adjusted blood pressure phenotypes within each of 10 subgroups defined by race and network. A modified Fisher's method was used to combine the P values for each linkage marker across the 10 subgroups. Results Five quantitative trait loci (QTLs) were detected on chromosomes 6p22.3, 8q23.1, 20q13.12, 21q21.1, and 21q21.3 based on significant linkage evidence (defined by logarithm of odds (lod) score ≥3) in at least one meta-analysis and lod scores ≥1 in at least 2 subgroups defined by network and race. The chromosome 8q23.1 locus was supported by Asian-, Caucasian-, and Mexican-American-specific meta-analyses. Conclusions The new QTLs reported justify new candidate gene studies. They may help support results from genome-wide association studies (GWAS) that fall in these QTL regions but fail to achieve the genome-wide significance. American Journal of Hypertension advance online publication 9 December 2010;doi:10.1038/ajh.2010.23

Five blood pressure loci identified by an updated genome-wide linkage scan: meta-analysis of the Family Blood Pressure Program

A preliminary genome-wide linkage analysis of blood pressure in the Family Blood Pressure Program (FBPP) was reported previously. We harnessed the power and ethnic diversity of the final pooled FBPP dataset to identify novel loci for blood pressure thereby enhancing localization of genes containing less common variants with large effects on blood pressure levels and hypertension