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

Cupples, L. Adrienne; Arruda, Heather T; Benjamin, Emelia J.; D’Agostino, Ralph B.; Demissie, Serkalem; DeStefano, Anita L.; Dupuis, Josée; Falls, Kathleen; Fox, Caroline S.; Gottlieb, Daniel J.; Govindaraju, Diddahally R.; Guo, Chao-Yu; Heard‐Costa, Nancy L.; Hwang, Shih‐Jen; Kathiresan, Sekar; Kiel, Douglas P.; Laramie, Jason M.; Larson, Martin G.; Levy, Daniel; Liu, Chunyu; Lunetta, Kathryn L.; Mailman, Matthew D.; Manning, Alisa K.; Meigs, James B.; Murabito, Joanne M.; Newton‐Cheh, Christopher; O’Connor, George T.; O’Donnell, Christopher J; Pandey, Mona; Seshadri, Sudha; Vasan, Ramachandran S.; Wang, Zhen Y; Wilk, Jemma B.; Wolf, Philip A.; Yang, Qiong; Atwood, Larry D.

doi:10.1186/1471-2350-8-s1-s1

Cited by 170 publications

(213 citation statements)

References 85 publications

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“…Recruitment of men and women from the town of Framingham, Massachusetts began in 1948 with the purpose of investigating the causes of cardiovascular disease and related traits. FHS investigators have recently published results of a 100K GWA study based on 1,345 subjects (310 pedigrees), 17 phenotypes, and the Affymetrix GeneChip Mapping 100K Array (11,26). All data were available through dbGaP.…”

Section: Methodsmentioning

confidence: 99%

Whole-genome association study identifies STK39 as a hypertension susceptibility gene

Wang

O’Connell

McArdle

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

273

270

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Hypertension places a major burden on individual and public health, but the genetic basis of this complex disorder is poorly understood. We conducted a genome-wide association study of systolic and diastolic blood pressure (SBP and DBP) in Amish subjects and found strong association signals with common variants in a serine/threonine kinase gene, STK39. We confirmed this association in an independent Amish and 4 non-Amish Caucasian samples including the Diabetes Genetics Initiative, Framingham Heart Study, GenNet, and Hutterites (meta-analysis combining all studies: n ‫؍‬ 7,125, P < 10 ؊6 ). The higher BP-associated alleles have frequencies > 0.09 and were associated with increases of 3.3/1.3 mm Hg in SBP/DBP, respectively, in the Amish subjects and with smaller but consistent effects across the non-Amish studies. Cellbased functional studies showed that STK39 interacts with WNK kinases and cation-chloride cotransporters, mutations in which cause monogenic forms of BP dysregulation. We demonstrate that in vivo, STK39 is expressed in the distal nephron, where it may interact with these proteins. Although none of the associated SNPs alter protein structure, we identified and experimentally confirmed a highly conserved intronic element with allele-specific in vitro transcription activity as a functional candidate for this association. Thus, variants in STK39 may influence BP by increasing STK39 expression and consequently altering renal Na ؉ excretion, thus unifying rare and common BP-regulating alleles in the same physiological pathway.blood pressure ͉ essential hypertension ͉ genome-wide association study ͉ SPAK ͉ STK39

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Section: Methodsmentioning

confidence: 99%

Whole-genome association study identifies STK39 as a hypertension susceptibility gene

Wang

O’Connell

McArdle

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

273

270

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“…Results of the Framingham heart study were similar to situations of the present study, and the authors reported that FBAT analysis was not significant because it was limited by the number of informative transmissions. 28 The results of haplotype GWAS using Monte Carlo permutation were significant after correction. Haplotype-based algorithms were developed to cope with multiple comparison problems in GWAS at multiple SNP loci in LD.…”

Section: Discussionmentioning

confidence: 99%

Genetic variants that affect length/height in infancy/early childhood in Vietnamese-Korean families

et al. 2010

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To identify genetic factors that influence height in infancy/early childhood , a family-based genome-wide association study was conducted using 269 888 single-nucleotide polymorphisms (SNPs) in 165 families composed of a Korean father, a Vietnamese mother and Vietnamese-Korean offspring in the International Marriage-based Immigrant Cohort in Korea. In a single-SNP-based analysis, the six SNPs in or near genes MAF, MAGI2, BMP4 and PTPN7 showed consistent suggestive associations at all height standard deviation scores using Korean, World Health Organization and Vietnamese growth references. Analyzing the haplotypes for the genes, haplotype blocks were found to be significantly associated with height. Similar to the results of a contiguous haplotype analysis using tag SNPs as above, noncontiguous haplotypes of variable length also showed a significant association near the suspected loci. Our result suggests that height during infancy/early childhood may be regulated by genetic variations that differ from those of adults.

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“…The other plausible scenario is informative missingness in the parents, but not the offspring, as seen in age-dependent diseases, such as cancer, 23 Parkinson's disease, 24 diabetes 25 and cardiovascular diseases. 26,27 Same as the TIM, the limitation of the TIMBD is that it could not detect informative missingness that exists solely in the offspring, but not the parents, which could be classified as ascertainment bias. However, the TIMBD could be the foundation and/or step stones for considering ascertainment bias in genetic studies, since it could determine whether or not parental genotypes are missing informatively.…”

Section: Discussionmentioning

confidence: 99%

A novel test of informative missingness using inconsistent linkage disequilibrium signals between case-parent triads and incomplete data

Guo

2012

J Hum Genet

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In general, multiple issues are examined before the analysis of genetic data such as Hardy-Weinberg Equilibrium and Mendelian errors. Although missing genotypes are commonly observed in genetic studies, potential bias due to informative missingness is usually overlooked. Therefore, the Test of Informative Missingness (TIM) was the first attempt to determine whether or not parental genotypes are missing informatively. The TIM is a useful tool for genetic data cleaning. For example, excluding single-nucleotide polymorphisms that appear to be missing informatively may further improve the quality of genetic data. Although the TIM has decent power, its performance is discernibly weaker when the minor allele/genotype introduces informative missingness. In an effort to avoid such reduced power, the newly proposed strategy detects informative missingness by comparing inconsistent linkage disequilibrium signals between intact case-parent triads and incomplete data. Computer simulations revealed that the new method was robust to population stratifications and more powerful than the TIM in most situations. In addition, the new method demonstrated decent power in the genome-wide association study, even if the most conservative correction for multiple testing was adopted. Keywords: case-parent triads; GWAS; HRR; informative missingness; TDT INTRODUCTION Spurious associations due to population admixture could be a serious issue in genetic studies using unrelated subjects. To avoid false signals, the family-based approach, haplotype relative risk (HRR), 1 utilizes case-parent triads to detect linkage disequilibrium (LD) between a marker and a putative disease locus by comparing parental marker alleles transmitted to an affected offspring to those non-transmitted. Instead of treating transmitted and non-transmitted alleles as unrelated, the Transmission/Disequilibrium Test (TDT) 2 considered case-parent triads as matched data and examined whether or not heterozygous parents preferentially transmitted the specific allele to the affected offspring. The TDT is more powerful than the HRR, especially when population admixture is present. Therefore, the TDT is a popular study design for early onset diseases.The greatest challenge in recruiting case-parent triads is that one or both parental genotypes may be unavailable due to declined participation, death, or other unexpected reasons. In the statistical analysis, both missing completely at random (MCAR) and missing at random (MAR) are ignorable. 3 If the events that lead to any particular value being missing are independent of both observed and unobserved parameters of interest, then the missing pattern is considered as MCAR. Given the observed data, if the missing mechanism does not depend on the unobserved data, then the missing pattern is MAR. The scenarios of MCAR and MAR could be confusing in the settings of a genetic study. For a single nucleotide polymorphism (SNP) with alleles A and C, there are three genotypes AA, AC and CC. In an admixed population, if the missing rates of ...

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

Cited by 170 publications

References 85 publications

Whole-genome association study identifies STK39 as a hypertension susceptibility gene

Whole-genome association study identifies STK39 as a hypertension susceptibility gene

Genetic variants that affect length/height in infancy/early childhood in Vietnamese-Korean families

A novel test of informative missingness using inconsistent linkage disequilibrium signals between case-parent triads and incomplete data

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