Framingham Heart Study Papers

On the Analysis of Genome-Wide Association Studies in Family-Based Designs: A Universal, Robust Analysis Approach and an Application to Four Genome-Wide Association Studies

2012-01-12T07:01:36Z

On the Analysis of Genome-Wide Association Studies in Family-Based Designs: A Universal, Robust Analysis Approach and an Application to Four Genome-Wide Association Studies Won, Sungho; Wilk, Jemma B.; Mathias, Rasika A.; O'Donnell, Christopher J.; Silverman, Edwin K.; Barnes, Kathleen; O'Connor, George T.; Weiss, Scott T.; Lange, Christoph For genome-wide association studies in family-based designs, we propose a new, universally applicable approach. The new test statistic exploits all available information about the association, while, by virtue of its design, it maintains the same robustness against population admixture as traditional family-based approaches that are based exclusively on the within-family information. The approach is suitable for the analysis of almost any trait type, e.g. binary, continuous, time-to-onset, multivariate, etc., and combinations of those. We use simulation studies to verify all theoretically derived properties of the approach, estimate its power, and compare it with other standard approaches. We illustrate the practical implications of the new analysis method by an application to a lung-function phenotype, forced expiratory volume in one second (FEV1) in 4 genome-wide association studies. Author Summary In genome-wide association studies, the multiple testing problem and confounding due to population stratification have been intractable issues. Family-based designs have considered only the transmission of genotypes from founder to nonfounder to prevent sensitivity to the population stratification, which leads to the loss of information. Here we propose a novel analysis approach that combines mutually independent FBAT and screening statistics in a robust way. The proposed method is more powerful than any other, while it preserves the complete robustness of family-based association tests, which only achieves much smaller power level. Furthermore, the proposed method is virtually as powerful as population-based approaches/designs, even in the absence of population stratification. By nature of the proposed method, it is always robust as long as FBAT is valid, and the proposed method achieves the optimal efficiency if our linear model for screening test reasonably explains the observed data in terms of covariance structure and population admixture. We illustrate the practical relevance of the approach by an application in 4 genome-wide association studies.

The impact of complex informative missingness on the validity of the transmission/disequilibrium test (TDT)

2012-01-12T07:00:35Z

The impact of complex informative missingness on the validity of the transmission/disequilibrium test (TDT) Guo, Chao-Yu The transmission/disequilibrium test was introduced to test for linkage and association between a marker and a putative disease locus using case-parent triads. Several extensions have been proposed to accommodate incomplete triads. Some strategies assumed that parental genotypes were missing completely at random and some methods allowed informative missingness for parental genotypes. However, the above tests assumed that offspring genotypes were missing completely at random and concluded that the transmission/disequilibrium test remained a valid test by excluding incomplete triads from the analysis. In this article, the conditional distribution of ascertained triads allowing informative missingness for offspring genotypes, as well as their parental genotypes, was derived and several tests under such scenarios were evaluated. In simulations, independent triads from the Genetic Analysis Workshop 15 simulated data (Problem 3) was ascertained. When offspring genotypes were missing informatively, simulation results revealed inflated type I error and/or reduced power for the transmission/disequilibrium test excluding incomplete triads.

Genome-Wide Association Studies of Serum Magnesium, Potassium, and Sodium Concentrations Identify Six Loci Influencing Serum Magnesium Levels

2012-01-12T07:00:22Z

Genome-Wide Association Studies of Serum Magnesium, Potassium, and Sodium Concentrations Identify Six Loci Influencing Serum Magnesium Levels Meyer, Tamra E.; Verwoert, Germaine C.; Hwang, Shih-Jen; Glazer, Nicole L.; Smith, Albert V.; van Rooij, Frank J. A.; Ehret, Georg B.; Boerwinkle, Eric; Felix, Janine F.; Leak, Tennille S.; Harris, Tamara B.; Yang, Qiong; Dehghan, Abbas; Aspelund, Thor; Katz, Ronit; Homuth, Georg; Kocher, Thomas; Rettig, Rainer; Ried, Janina S.; Gieger, Christian; Prucha, Hanna; Pfeufer, Arne; Meitinger, Thomas; Coresh, Josef; Hofman, Albert; Sarnak, Mark J.; Chen, Yii-Der Ida; Uitterlinden, André G.; Chakravarti, Aravinda; Psaty, Bruce M.; van Duijn, Cornelia M.; Kao, W. H. Linda; Witteman, Jacqueline C. M.; Gudnason, Vilmundur; Siscovick, David S.; Fox, Caroline S.; Köttgen, Anna Magnesium, potassium, and sodium, cations commonly measured in serum, are involved in many physiological processes including energy metabolism, nerve and muscle function, signal transduction, and fluid and blood pressure regulation. To evaluate the contribution of common genetic variation to normal physiologic variation in serum concentrations of these cations, we conducted genome-wide association studies of serum magnesium, potassium, and sodium concentrations using ∼2.5 million genotyped and imputed common single nucleotide polymorphisms (SNPs) in 15,366 participants of European descent from the international CHARGE Consortium. Study-specific results were combined using fixed-effects inverse-variance weighted meta-analysis. SNPs demonstrating genome-wide significant (p<5×10−8) or suggestive associations (p<4×10−7) were evaluated for replication in an additional 8,463 subjects of European descent. The association of common variants at six genomic regions (in or near MUC1, ATP2B1, DCDC5, TRPM6, SHROOM3, and MDS1) with serum magnesium levels was genome-wide significant when meta-analyzed with the replication dataset. All initially significant SNPs from the CHARGE Consortium showed nominal association with clinically defined hypomagnesemia, two showed association with kidney function, two with bone mineral density, and one of these also associated with fasting glucose levels. Common variants in CNNM2, a magnesium transporter studied only in model systems to date, as well as in CNNM3 and CNNM4, were also associated with magnesium concentrations in this study. We observed no associations with serum sodium or potassium levels exceeding p<4×10−7. Follow-up studies of newly implicated genomic loci may provide additional insights into the regulation and homeostasis of human serum magnesium levels. Author Summary Magnesium, potassium, and sodium are involved in important physiological processes. To better understand how common genetic variation may contribute to inter-individual differences in serum concentrations of these electrolytes, we evaluated single nucleotide polymorphisms (SNPs) across the genome in association with serum magnesium, potassium, and sodium levels in 15,366 participants of European descent from the CHARGE Consortium. We then verified the associations in an additional 8,463 study participants. Six different genomic regions contain variants that are reproducibly associated with serum magnesium levels, and only one of the regions had been previously known to influence serum magnesium concentrations in humans. The identified SNPs also show association with clinically defined hypomagnesemia, and some of them with traits that have been linked to serum magnesium levels, including kidney function, fasting glucose, and bone mineral density. We further provide evidence for a physiological role of magnesium transporters in humans which have previously only been studied in model systems. None of the SNPs evaluated in our study are significantly associated with serum levels of sodium or potassium. Additional studies are needed to investigate the underlying molecular mechanisms in order to help us understand the contribution of these newly identified regions to magnesium homeostasis.

Forty-Three Loci Associated with Plasma Lipoprotein Size, Concentration, and Cholesterol Content in Genome-Wide Analysis

2012-01-12T07:00:20Z

Forty-Three Loci Associated with Plasma Lipoprotein Size, Concentration, and Cholesterol Content in Genome-Wide Analysis Chasman, Daniel I.; Paré, Guillaume; Mora, Samia; Hopewell, Jemma C.; Peloso, Gina; Clarke, Robert; Cupples, L. Adrienne; Hamsten, Anders; Kathiresan, Sekar; Mälarstig, Anders; Ordovas, José M.; Ripatti, Samuli; Parker, Alex N.; Miletich, Joseph P.; Ridker, Paul M. While conventional LDL-C, HDL-C, and triglyceride measurements reflect aggregate properties of plasma lipoprotein fractions, NMR-based measurements more accurately reflect lipoprotein particle concentrations according to class (LDL, HDL, and VLDL) and particle size (small, medium, and large). The concentrations of these lipoprotein sub-fractions may be related to risk of cardiovascular disease and related metabolic disorders. We performed a genome-wide association study of 17 lipoprotein measures determined by NMR together with LDL-C, HDL-C, triglycerides, ApoA1, and ApoB in 17,296 women from the Women's Genome Health Study (WGHS). Among 36 loci with genome-wide significance (P<5×10−8) in primary and secondary analysis, ten (PCCB/STAG1 (3q22.3), GMPR/MYLIP (6p22.3), BTNL2 (6p21.32), KLF14 (7q32.2), 8p23.1, JMJD1C (10q21.3), SBF2 (11p15.4), 12q23.2, CCDC92/DNAH10/ZNF664 (12q24.31.B), and WIPI1 (17q24.2)) have not been reported in prior genome-wide association studies for plasma lipid concentration. Associations with mean lipoprotein particle size but not cholesterol content were found for LDL at four loci (7q11.23, LPL (8p21.3), 12q24.31.B, and LIPG (18q21.1)) and for HDL at one locus (GCKR (2p23.3)). In addition, genetic determinants of total IDL and total VLDL concentration were found at many loci, most strongly at LIPC (15q22.1) and APOC-APOE complex (19q13.32), respectively. Associations at seven more loci previously known for effects on conventional plasma lipid measures reveal additional genetic influences on lipoprotein profiles and bring the total number of loci to 43. Thus, genome-wide associations identified novel loci involved with lipoprotein metabolism—including loci that affect the NMR-based measures of concentration or size of LDL, HDL, and VLDL particles—all characteristics of lipoprotein profiles that may impact disease risk but are not available by conventional assay. Author Summary Genome-wide association studies (GWAS) of plasma lipoprotein fractions hold great promise for understanding lipid metabolism and its central role in cardiovascular disease and related disorders. Conventional assays for lipoprotein status determine total cholesterol content of low- or high-density lipoprotein particles (LDL-C or HDL-C, respectively) or total plasma triglyceride content (as an estimate of very-low density lipoprotein particle concentration [VLDL]). All three measures have been targets for recent GWAS. However, a more precise target for GWAS of lipoprotein metabolism would be the concentration of the individual lipoprotein particles according to class (LDL, HDL, VLDL) and size (small, medium, and large), all of which can be measured by NMR-based methods. In a population of 17,296 women of European ancestry from the Women's Genome Health Study, we have performed a GWAS for 22 lipoprotein measures derived from NMR-based and conventional assays. We find 43 genetic loci involved in lipoprotein metabolism, including 10 novel loci. The results offer a clearer picture of common genetic influences on lipoprotein metabolism than available previously, including genetic effects on the distribution of LDL, HDL, and VLDL particle size, as well as on IDL and VLDL particle concentration, neither of which can be assessed by conventional measures.