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Detection of imprinting and heterogeneous maternal effects on high blood pressure using Framingham Heart Study data.

ABSTRACT: Both imprinting and maternal effects could lead to parent-of-origin patterns in complex traits of human disorders. Statistical methods that differentiate these two effects and identify them simultaneously by using family-based data from retrospective studies are available. The usual data structures include case-parents triads and nuclear families with multiple affected siblings. We develop a likelihood-based method to detect imprinting and maternal effects simultaneously using data from prospective studies. The proposed method utilizes both affected and unaffected siblings in nuclear families by modeling familial genotypes and offspring's disease status jointly. Maternal effect is usually modeled as a fixed effect under the assumption that maternal variant allele(s) has (have) identical effect on any offspring. However, recent studies report that different people may carry different amounts of substances encoded by the mother's variant allele(s) (called maternal microchimerism), which could result in heterogeneity of maternal effects. The proposed method incorporates the heterogeneity of maternal effects by adding a random component to the logit of the penetrance. Our method was applied to the Framingham Heart Study data in two steps to detect single-nucleotide polymorphisms (SNPs) that may be associated with high blood pressure. In the first step, SNPs that affect susceptibility of high blood pressure through minor allele, genomic imprinting, or maternal effects were identified by using the proposed model without the random effect component. In the second step, we fitted the mixed effect model to the identified SNPs that have significant maternal effect to detect heterogeneity of the maternal effects.

SUBMITTER: Yang J

PROVIDER: S-EPMC2795898 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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Detection of imprinting and heterogeneous maternal effects on high blood pressure using Framingham Heart Study data.

Yang Jingyuan J Lin Shili S

BMC proceedings 20091215

Both imprinting and maternal effects could lead to parent-of-origin patterns in complex traits of human disorders. Statistical methods that differentiate these two effects and identify them simultaneously by using family-based data from retrospective studies are available. The usual data structures include case-parents triads and nuclear families with multiple affected siblings. We develop a likelihood-based method to detect imprinting and maternal effects simultaneously using data from prospect ...[more]

PMID: 20017991

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Project description:About one quarter of adults are hypertensive and high blood pressure carries increased risk for heart disease, stroke, kidney disease and death. Increased arterial stiffness is a key factor in the pathogenesis of systolic hypertension and cardiovascular disease. Substantial heritability of blood-pressure (BP) and arterial-stiffness suggests important genetic contributions.In Framingham Heart Study families, we analyzed genome-wide SNP (Affymetrix 100K GeneChip) associations with systolic (SBP) and diastolic (DBP) BP at a single examination in 1971-1975 (n = 1260), at a recent examination in 1998-2001 (n = 1233), and long-term averaged SBP and DBP from 1971-2001 (n = 1327, mean age 52 years, 54% women) and with arterial stiffness measured by arterial tonometry (carotid-femoral and carotid-brachial pulse wave velocity, forward and reflected pressure wave amplitude, and mean arterial pressure; 1998-2001, n = 644). In primary analyses we used generalized estimating equations in models for an additive genetic effect to test associations between SNPs and phenotypes of interest using multivariable-adjusted residuals. A total of 70,987 autosomal SNPs with minor allele frequency > or = 0.10, genotype call rate > or = 0.80, and Hardy-Weinberg equilibrium p > or = 0.001 were analyzed. We also tested for association of 69 SNPs in six renin-angiotensin-aldosterone pathway genes with BP and arterial stiffness phenotypes as part of a candidate gene search.In the primary analyses, none of the associations attained genome-wide significance. For the six BP phenotypes, seven SNPs yielded p values < 10(-5). The lowest p-values for SBP and DBP respectively were rs10493340 (p = 1.7 x 10(-6)) and rs1963982 (p = 3.3 x 10(-6)). For the five tonometry phenotypes, five SNPs had p values < 10(-5); lowest p-values were for reflected wave (rs6063312, p = 2.1 x 10(-6)) and carotid-brachial pulse wave velocity (rs770189, p = 2.5 x 10(-6)) in MEF2C, a regulator of cardiac morphogenesis. We found only weak association of SNPs in the renin-angiotensin-aldosterone pathway with BP or arterial stiffness.These results of genome-wide association testing for blood pressure and arterial stiffness phenotypes in an unselected community-based sample of adults may aid in the identification of the genetic basis of hypertension and arterial disease, help identify high risk individuals, and guide novel therapies for hypertension. Additional studies are needed to replicate any associations identified in these analyses.

Dataset Information

Detection of imprinting and heterogeneous maternal effects on high blood pressure using Framingham Heart Study data.

Publications

Detection of imprinting and heterogeneous maternal effects on high blood pressure using Framingham Heart Study data.

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