Genome-Wide Association with Select Biomarker Traits in the Framingham Heart Study

BACKGROUND: Systemic biomarkers provide insights into disease pathogenesis, diagnosis, and risk stratification. Many systemic biomarker concentrations are heritable phenotypes. Genome-wide association studies (GWAS) provide mechanisms to investigate the genetic contributions to biomarker variability unconstrained by current knowledge of physiological relations. METHODS: We examined the association of Affymetrix 100K GeneChip single nucleotide polymorphisms (SNPs) to 22 systemic biomarker concentrations in 4 biological domains: inflammation/oxidative stress; natriuretic peptides; liver function; and vitamins. Related members of the Framingham Offspring cohort (n = 1012; mean age 59 ± 10 years, 51% women) had both phenotype and genotype data (minimum-maximum per phenotype n = 507–1008). We used Generalized Estimating Equations (GEE), Family Based Association Tests (FBAT) and variance components linkage to relate SNPs to multivariable-adjusted biomarker residuals. Autosomal SNPs (n = 70,987) meeting the following criteria were studied: minor allele frequency ≥ 10%, call rate ≥ 80% and Hardy-Weinberg equilibrium p ≥ 0.001. RESULTS: With GEE, 58 SNPs had p < 10-6: the top SNPs were rs2494250 (p = 1.00*10-14) and rs4128725 (p = 3.68*10-12) for monocyte chemoattractant protein-1 (MCP1), and rs2794520 (p = 2.83*10-8) and rs2808629 (p = 3.19*10-8) for C-reactive protein (CRP) averaged from 3 examinations (over about 20 years). With FBAT, 11 SNPs had p < 10-6: the top SNPs were the same for MCP1 (rs4128725, p = 3.28*10-8, and rs2494250, p = 3.55*10-8), and also included B-type natriuretic peptide (rs437021, p = 1.01*10-6) and Vitamin K percent undercarboxylated osteocalcin (rs2052028, p = 1.07*10-6). The peak LOD (logarithm of the odds) scores were for MCP1 (4.38, chromosome 1) and CRP (3.28, chromosome 1; previously described) concentrations; of note the 1.5 support interval included the MCP1 and CRP SNPs reported above (GEE model). Previous candidate SNP associations with circulating CRP concentrations were replicated at p < 0.05; the SNPs rs2794520 and rs2808629 are in linkage disequilibrium with previously reported SNPs. GEE, FBAT and linkage results are posted at . CONCLUSION: The Framingham GWAS represents a resource to describe potentially novel genetic influences on systemic biomarker variability. The newly described associations will need to be replicated in other studies.National Heart, Lung, and Blood Institute's Framingham Heart Study (N01-HC25195); National Institutes of Health National Center for Research Resources Shared Instrumentation grant (1S10RR163736-01A1); National Institutes of Health (HL064753, HL076784, AG028321, HL71039, 2 K24HL04334, 1K23 HL083102); Doris Duke Charitable Foundation; American Diabetes Association Career Developement Award; National Center for Research Resources (GCRC M01-RR01066); US Department of Agriculture Agricultural Research Service (58-1950-001, 58-1950-401); National Institute of Aging (AG14759

The GH receptor exon 3 deletion is a marker of male-specific exceptional longevity associated with increased GH sensitivity and taller stature

Although both growth hormone (GH) and insulin-like growth factor 1 (IGF-1) signaling were shown to regulate life span in lower organisms, the role of GH signaling in human longevity remains unclear. Because a GH receptor exon 3 deletion (d3-GHR) appears to modulate GH sensitivity in humans, we hypothesized that this polymorphism could play a role in human longevity. We report a linear increased prevalence of d3-GHR homozygosity with age in four independent cohorts of long-lived individuals: 841 participants [567 of the Longevity Genes Project (LGP) (8% increase; P = 0.01), 152 of the Old Order Amish (16% increase; P = 0.02), 61 of the Cardiovascular Health Study (14.2% increase; P = 0.14), and 61 of the French Long-Lived Study (23.5% increase; P = 0.02)]. In addition, mega analysis of males in all cohorts resulted in a significant positive trend with age (26% increase; P = 0.007), suggesting sexual dimorphism for GH action in longevity. Further, on average, LGP d3/d3 homozygotes were 1 inch taller than the wild-type (WT) allele carriers (P = 0.05) and also showed lower serum IGF-1 levels (P = 0.003). Multivariate regression analysis indicated that the presence of d3/d3 genotype adds approximately 10 years to life span. The LGP d3/d3-GHR transformed lymphocytes exhibited superior growth and extracellular signal–regulated kinase activation, to GH treatment relative to WT GHR lymphocytes (P < 0.01), indicating a GH dose response. The d3-GHR variant is a common genetic polymorphism that modulates GH responsiveness throughout the life span and positively affects male longevity

Framingham Heart Study 100K project: genome-wide associations for cardiovascular disease outcomes

BACKGROUND:Cardiovascular disease (CVD) and its most common manifestations - including coronary heart disease (CHD), stroke, heart failure (HF), and atrial fibrillation (AF) - are major causes of morbidity and mortality. In many industrialized countries, cardiovascular disease (CVD) claims more lives each year than any other disease. Heart disease and stroke are the first and third leading causes of death in the United States. Prior investigations have reported several single gene variants associated with CHD, stroke, HF, and AF. We report a community-based genome-wide association study of major CVD outcomes.METHODS:In 1345 Framingham Heart Study participants from the largest 310 pedigrees (54% women, mean age 33 years at entry), we analyzed associations of 70,987 qualifying SNPs (Affymetrix 100K GeneChip) to four major CVD outcomes: major atherosclerotic CVD (n = 142; myocardial infarction, stroke, CHD death), major CHD (n = 118; myocardial infarction, CHD death), AF (n = 151), and HF (n = 73). Participants free of the condition at entry were included in proportional hazards models. We analyzed model-based deviance residuals using generalized estimating equations to test associations between SNP genotypes and traits in additive genetic models restricted to autosomal SNPs with minor allele frequency [greater than or equal to]0.10, genotype call rate [greater than or equal to]0.80, and Hardy-Weinberg equilibrium p-value [greater than or equal to] 0.001.RESULTS:Six associations yielded p <10-5. The lowest p-values for each CVD trait were as follows: major CVD, rs499818, p = 6.6 x 10-6; major CHD, rs2549513, p = 9.7 x 10-6; AF, rs958546, p = 4.8 x 10-6; HF: rs740363, p = 8.8 x 10-6. Of note, we found associations of a 13 Kb region on chromosome 9p21 with major CVD (p 1.7 - 1.9 x 10-5) and major CHD (p 2.5 - 3.5 x 10-4) that confirm associations with CHD in two recently reported genome-wide association studies. Also, rs10501920 in CNTN5 was associated with AF (p = 9.4 x 10-6) and HF (p = 1.2 x 10-4). Complete results for these phenotypes can be found at the dbgap website http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007.CONCLUSION:No association attained genome-wide significance, but several intriguing findings emerged. Notably, we replicated associations of chromosome 9p21 with major CVD. Additional studies are needed to validate these results. Finding genetic variants associated with CVD may point to novel disease pathways and identify potential targeted preventive therapies

The Framingham Heart Study 100K SNP genome-wide association study resource: overview of 17 phenotype working group reports

Background: The Framingham Heart Study (FHS), founded in 1948 to examine the epidemiology of cardiovascular disease, is among the most comprehensively characterized multi-generational studies in the world. Many collected phenotypes have substantial genetic contributors; yet most genetic determinants remain to be identified. Using single nucleotide polymorphisms (SNPs) from a 100K genome-wide scan, we examine the associations of common polymorphisms with phenotypic variation in this community-based cohort and provide a full-disclosure, web-based resource of results for future replication studies. Methods: Adult participants (n = 1345) of the largest 310 pedigrees in the FHS, many biologically related, were genotyped with the 100K Affymetrix GeneChip. These genotypes were used to assess their contribution to 987 phenotypes collected in FHS over 56 years of follow up, including: cardiovascular risk factors and biomarkers; subclinical and clinical cardiovascular disease; cancer and longevity traits; and traits in pulmonary, sleep, neurology, renal, and bone domains. We conducted genome-wide variance components linkage and population-based and family-based association tests. Results: The participants were white of European descent and from the FHS Original and Offspring Cohorts (examination 1 Offspring mean age 32 ± 9 years, 54% women). This overview summarizes the methods, selected findings and limitations of the results presented in the accompanying series of 17 manuscripts. The presented association results are based on 70,897 autosomal SNPs meeting the following criteria: minor allele frequency ≥ 10%, genotype call rate ≥ 80%, Hardy-Weinberg equilibrium p-value ≥ 0.001, and satisfying Mendelian consistency. Linkage analyses are based on 11,200 SNPs and short-tandem repeats. Results of phenotype-genotype linkages and associations for all autosomal SNPs are posted on the NCBI dbGaP website at http:// www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007. Conclusion: We have created a full-disclosure resource of results, posted on the dbGaP website, from a genome-wide association study in the FHS. Because we used three analytical approaches to examine the association and linkage of 987 phenotypes with thousands of SNPs, our results must be considered hypothesis-generating and need to be replicated. Results from the FHS 100K project with NCBI web posting provides a resource for investigators to identify high priority findings for replication.Molecular and Cellular Biolog

An elucidation of over a century old enigma in genetics-Heterosis.

Recognition and exploitation of hybrid vigor or heterosis among individual crosses of plants and animals has a long and distinguished history. Its manifestation is influenced by a combination of genetic, epigenetic, phenotypic, and environmental factors. Although heterosis is known to be governed by both dominant and epistatic gene action, its expression is greatly influenced by nonlinear interaction among epigenetic and phenotypic (phenomic) components. The magnitude of heterosis is generally inferred post hoc by the phenotypic performance of hybrids among laboriously made individual crosses. The expression of dominance, however, is nonlinear at the cellular level and obeys the principles underlying metabolic flux. Then, is it possible to exploit these relationships to predict heterosis? Vasseur and colleagues have indeed demonstrated the feasibility of such an approach in a series of experiments taking integrated biochemical and computational approaches, as well as testing these results on large samples of model organisms. The results offer promise toward phenomic prediction of heterosis across a wide array of organisms

Application of Smart Infrastructure Systems approach to precision medicine

All biological variation is hierarchically organized dynamic network system of genomic components, organelles, cells, tissues, organs, individuals, families, populations and metapopulations. Individuals are axial in this hierarchy, as they represent antecedent, attendant and anticipated aspects of health, disease, evolution and medical care. Humans show individual specific genetic and clinical features such as complexity, cooperation, resilience, robustness, vulnerability, self-organization, latent and emergent behavior during their development, growth and senescence. Accurate collection, measurement, organization and analyses of individual specific data, embedded at all stratified levels of biological, demographic and cultural diversity – the big data – is necessary to make informed decisions on health, disease and longevity; which is a central theme of precision medicine initiative (PMI). This initiative also calls for the development of novel analytical approaches to handle complex multidimensional data. Here we suggest the application of Smart Infrastructure Systems (SIS) approach to accomplish some of the goals set forth by the PMI on the premise that biological systems and the SIS share many common features. The latter has been successfully employed in managing complex networks of non-linear adaptive controls, commonly encountered in smart engineering systems. We highlight their concordance and discuss the utility of the SIS approach in precision medicine programs

The Muller’s Ratchet and Aging

Aging entails an irreversible deceleration of physiological processes, altered metabolic activities, and a decline of the integrity of tissues, organs, and organ systems. The accumulation of alterations in the genetic and epigenetic spaces has been proposed as an explanation for aging. They result, at least in part, from DNA replication and chromosome segregation errors due to cell division during development, growth, renewal, and repair. Such deleterious alterations, including epigenetic drift, irreversibly accumulate in a stepwise, ratchet-like manner and reduce cellular fitness, similar to the process known as Muller’s ratchet. Here, we revisit the Muller’s ratchet principle applied to the aging of somatic cell populations and discuss the implications for understanding the origins of senescence, frailty, and morbidity

Linkage Disequilibria and Haplotype Structure of Four SNPs of the Interleukin 1 Gene Cluster in Seven Asian Indian Populations

Variation at four single nucleotide polymorphism (SNP) sites of the interleukin 1 (IL1) gene cluster was investigated among 280 unrelated individuals, representing 7 caste groups from the state of Karnataka, India, and one European American community of Boston, Massachusetts. Allele and haplotype frequencies, strength of linkage disequilibrium, and signatures of recombination varied considerably among populations. Variable community sizes and traditions of consanguinity may account for the observed variation