Faculty Bibliography

We conducted meta-analyses of genome-wide association studies for atrial fibrillation (AF) in participants from five community-based cohorts. Meta-analyses of 896 prevalent (15,768 referents) and 2,517 incident (21,337 referents) AF cases identified a new locus for AF (ZFHX3, rs2106261, risk ratio RR = 1.19; P = 2.3 x 10(-7)). We replicated this association in an independent cohort from the German AF Network (odds ratio = 1.44; P = 1.6 x 10(-11); combined RR = 1.25; combined P = 1.8 x 10(-15)).

Essential hypertension is a major cardiovascular risk factor and a large proportion of this risk is genetic. Identification of genomic regions consistently associated with hypertension has been difficult in association studies to date as this requires large sample sizes.We previously published a large genome-wide linkage scan in Americans of African (AA) and European (EA) descent in the GenNet Network of the Family Blood Pressure Program (FBPP). A highly significant linkage peak was identified on chr1q spanning a region of 100 cM. In this study, we genotyped 1569 SNPs under this linkage peak in 2379 individuals to identify whether common genetic variants were associated with blood pressure (BP) at this locus.Our analysis, using two different family-based association tests, provides suggestive evidence (P< or =2 x 10(-5)) for a collection of single nucleotide polymorphisms (SNPs) associated with BP. In EAs, using diastolic BP as a quantitative phenotype, three variants located in or near the GPA33, CD247, and F5 genes, emerge as our top hits; for systolic BP, variants in GPA33, CD247, and REN are our best findings. No variant in AAs came close to suggestive evidence after multiple-test corrections (P> or =8 x 10(-5)). In summary, we show that systematic follow-up of a linkage signal can help discover candidate variants for essential hypertension that require a follow-up in yet larger samples. The failure to identify common variants is either because of low statistical power or the existence of rare coding variants in specific families or both, which require additional studies to clarify.

BACKGROUND: Age-related macular degeneration (AMD), a chronic neurodegenerative and neovascular retinal disease, is the leading cause of blindness in elderly people of western European origin. While structural and functional alterations in mitochondria (mt) and their metabolites have been implicated in the pathogenesis of chronic neurodegenerative and vascular diseases, the relationship of inherited variants in the mitochondrial genome and mt haplogroup subtypes with advanced AMD has not been reported in large prospective cohorts. METHODOLOGY/PRINICIPAL FINDINGS: We examined the relationship of inherited mtDNA variants with advanced AMD in 1168 people using a three-stage design on samples from 12-year and 10-year prospective studies on the natural history of age-related eye disease. In Stage I we resequenced the entire genome in 99 elderly AMD-free controls and 215 people with advanced AMD from the 12-year study. A consistent association with AMD in 14 of 17 SNPs characterizing the mtDNA T haplogroup emerged. Further analysis revealed these associations were driven entirely by the T2 haplogroup, and characterized by two variants in Complex I genes (A11812G of MT-ND4 and A14233G of MT-ND6). We genotyped T haplogroups in an independent sample of 490 cases and 61 controls from the same study (Stage II) and in 56 cases and 246 controls from the 10-year study (Stage III). People in the T2 haplogroup were approximately 2.5 times more likely to have advanced AMD than their peers (odds ratio [OR] = 2.54, 95%CI 1.36-4.80, P

PMCID:2677106

PMID: 19434233

ISSN: 1932-6203

CID: 2747552