Showing papers by "Michael A. Province published in 2009"

Avoiding the high Bonferroni penalty in genome-wide association studies.

Abstract: A major challenge in genome-wide association studies (GWASs) is to derive the multiple testing threshold when hypothesis tests are conducted using a large number of single nucleotide polymorphisms. Permutation tests are considered the gold standard in multiple testing adjustment in genetic association studies. However, it is computationally intensive, especially for GWASs, and can be impractical if a large number of random shuffles are used to ensure accuracy. Many researchers have developed approximation algorithms to relieve the computing burden imposed by permutation. One particularly attractive alternative to permutation is to calculate the effective number of independent tests, M(eff), which has been shown to be promising in genetic association studies. In this study, we compare recently developed M(eff) methods and validate them by the permutation test with 10,000 random shuffles using two real GWAS data sets: an Illumina 1M BeadChip and an Affymetrix GeneChip Human Mapping 500K Array Set. Our results show that the simpleM method produces the best approximation of the permutation threshold, and it does so in the shortest amount of time. We also show that M(eff) is indeed valid on a genome-wide scale in these data sets based on statistical theory and significance tests. The significance thresholds derived can provide practical guidelines for other studies using similar population samples and genotyping platforms.

NRXN3 is a novel locus for waist circumference: a genome-wide association study from the CHARGE Consortium.

Abstract: Central abdominal fat is a strong risk factor for diabetes and cardiovascular disease. To identify common variants influencing central abdominal fat, we conducted a two-stage genome-wide association analysis for waist circumference (WC). In total, three loci reached genome-wide significance. In stage 1, 31,373 individuals of Caucasian descent from eight cohort studies confirmed the role of FTO and MC4R and identified one novel locus associated with WC in the neurexin 3 gene [NRXN3 (rs10146997, p = 6.4610 27 )]. The association with NRXN3 was confirmed in stage 2 by combining stage 1 results with those from 38,641 participants in the GIANT consortium (p = 0.009 in GIANT only, p = 5.3610 28 for combined analysis, n = 70,014). Mean WC increase per copy of the G allele was 0.0498 z-score units (0.65 cm). This SNP was also associated with body mass index (BMI) [p = 7.4610 26 , 0.024 z-score units (0.10 kg/m 2 ) per copy of the G allele] and the risk of obesity (odds ratio 1.13, 95% CI 1.07–1.19; p = 3.2610 25 per copy of the G allele). The NRXN3 gene has been previously implicated in addiction and reward behavior, lending further evidence that common forms of obesity may be a central nervous system-mediated disorder. Our findings establish that common variants in NRXN3 are associated with WC, BMI, and obesity.

A Family Longevity Selection Score: Ranking Sibships by Their Longevity, Size, and Availability for Study

Abstract: Family studies of exceptional longevity can potentially identify genetic and other factors contributing to long life and healthy aging. Although such studies seek families that are exceptionally long lived, they also need living members who can provide DNA and phenotype information. On the basis of these considerations, the authors developed a metric to rank families for selection into a family study of longevity. Their measure, the family longevity selection score (FLoSS), is the sum of 2 components: 1) an estimated family longevity score built from birth-, gender-, and nation-specific cohort survival probabilities and 2) a bonus for older living siblings. The authors examined properties of FLoSS-based family rankings by using data from 3 ongoing studies: the New England Centenarian Study, the Framingham Heart Study, and screenees for the Long Life Family Study. FLoSS-based selection yields families with exceptional longevity, satisfactory sibship sizes and numbers of living siblings, and high ages. Parameters in the FLoSS formula can be tailored for studies of specific populations or age ranges or with different conditions. The first component of the FLoSS also provides a conceptually sound survival measure to characterize exceptional longevity in individuals or families in various types of studies and correlates well with later-observed longevity.

ADIPOQ Polymorphisms, Monounsaturated Fatty Acids, and Obesity Risk: The GOLDN Study

Abstract: Serum adiponectin levels have been positively associated with insulin sensitivity and are decreased in type 2 diabetes (T2D) and obesity. Genetic and environmental factors influence serum adiponectin and may contribute to risk of metabolic syndrome and T2D. Therefore, we investigated the effect of ADIPOQ single-nucleotide polymorphisms (SNPs), -11377C>G and -11391G>A, on metabolic-related traits, and their modulation by dietary fat in white Americans. Data were collected from 1,083 subjects participating in the Genetics of Lipid Lowering Drugs and Diet Network study. Mean serum adiponectin concentration was higher for carriers of the -11391A allele (P = 0.001) but lower for the -11377G allele carriers (P = 0.017). Moreover, we found a significant association with obesity traits for the -11391G>A SNP. Carriers of the -11391A allele had significantly lower weight (P = 0.029), BMI (P = 0.019), waist (P = 0.003), and hip circumferences (P = 0.004) compared to noncarriers. Interestingly, the associations of the -11391G>A with BMI and obesity risk were modified by monounsaturated fatty acids (MUFAs) intake (P-interaction = 0.021 and 0.034 for BMI and obesity risk, respectively). In subjects with MUFA intake above the median (> or =13% of energy intake), -11391A carriers had lower BMI (27.1 kg/m(2) for GA+AA vs. 29.1 kg/m(2) for GG, P = 0.002) and decreased obesity risk (odds ratio for -11391A = 0.52, 95% confidence interval (CI); 0.28-0.96; P = 0.031). However, we did not detect genotype-related differences for BMI or obesity in subjects with MUFA intake A SNPs and obesity-related traits and the potential to moderate such effects using dietary modification.

Leptin Is Associated With Blood Pressure and Hypertension in Women From the National Heart, Lung, and Blood Institute Family Heart Study

Abstract: Leptin is a key neuroendocrine hormone regulating food intake, metabolism, and fat accumulation, and it may also affect blood pressure and contribute to hypertension through sympathetic activation in the vasculature or at the renal level. Although previous studies have shown that the distribution of leptin is significantly different between males and females, as is the risk of hypertension between males and females, results regarding the role of leptin in the gender-specific regulation of blood pressure are controversial. Thus, we performed family-based association analyses in the National Heart, Lung, and Blood Institute Family Heart Study to test the hypothesis that LEPTIN gene variants and the plasma leptin level influence variability in blood pressure and the risk of hypertension differently by gender. We identified significant associations between LEPTIN single nucleotide polymorphisms with blood pressure and hypertension, but in postmenopausal women only. We also identified significant associations between plasma leptin levels and both blood pressure and hypertension in women. The current study supports a role for LEPTIN and plasma leptin levels in blood pressure regulation in women. It also provides insight into the gender differences in hypertension, as well as the differential distribution and activity of leptin in men and women.

Pharmacogenetic association of the APOA1/C3/A4/A5 gene cluster and lipid responses to fenofibrate: the genetics of lipid-lowering drugs and diet network study.

Abstract: BackgroundThe apolipoproteins (APOA1/C3/A4/A5) are key components in modulating lipoprotein metabolism. It is unknown whether variants at the APOA1/C3/A4/A5 gene cluster are associated with lipid response to pharmacologic intervention.Methods and resultsPlasma triglycerides (TGs) and high-density li

Polyunsaturated fatty acids modulate the effect of TCF7L2 gene variants on postprandial lipemia

Abstract: The transcription factor 7-like 2 (TCF7L2) has been recently associated with diabetes risk, and it may exert its effect through metabolic syndrome (MetS)-related traits and be subjected to modification by environmental factors. We investigated the effect of single nucleotide polymorphisms (SNP), rs7903146 and rs12255372, within the TCF7L2 locus on postprandial lipemia and other MetS-related traits and their modulation by dietary fat. Data were collected from 1083 European Americans participating in the Genetics of Lipid Lowering Drugs and Diet Network Study. Carriers of the minor T allele at the C/T rs7903146 SNP had higher fasting plasma glucose (P = 0.012), lower homeostasis model assessment of beta cell function (P = 0.041), higher plasma VLDL (P = 0.035), and lower large LDL particle (P = 0.007) concentrations and higher risk of MetS (P = 0.011) than CC individuals. Moreover, we identified significant interactions between this SNP and PUFA intake modulating fasting VLDL particle concentrations (P = 0.016) and postprandial triglycerides (TG) (P = 0.028), chylomicrons (P = 0.025), total VLDL (P = 0.026), and large VLDL (P = 0.018) concentrations. Thus, only T allele carriers with a PUFA intake > or = 7.36% of energy had elevated fasting plasma VLDL concentrations and postprandial TG-rich lipoproteins. These variables did not differ in T allele carriers and noncarriers in the low-PUFA intake group. Moreover, these significant interactions were due exclusively to (n-6) PUFA intake. In summary, high (n-6) PUFA intakes (> or = 6.62% of energy intake) were associated with atherogenic dyslipidemia in carriers of the minor T allele at the TCF7L2 rs7903146 SNP and may predispose them to MetS, diabetes, and cardiovascular disease.

The Genetic Analysis Workshop 16 Problem 3: simulation of heritable longitudinal cardiovascular phenotypes based on actual genome-wide single-nucleotide polymorphisms in the Framingham Heart Study

Abstract: The Genetic Analysis Workshop (GAW) 16 Problem 3 comprises simulated phenotypes emulating the lipid domain and its contribution to cardiovascular disease risk. For each replication there were 6,476 subjects in families from the Framingham Heart Study (FHS), with their actual genotypes for Affymetrix 550 k single-nucleotide polymorphisms (SNPs) and simulated phenotypes. Phenotypes are simulated at three visits, 10 years apart. There are up to 6 "major" genes influencing variation in high- and low-density lipoprotein cholesterol (HDL, LDL), and triglycerides (TG), and 1,000 "polygenes" simulated for each trait. Some polygenes have pleiotropic effects. The locus-specific heritabilities of the major genes range from 0.1 to 1.0%, under additive, dominant, or overdominant modes of inheritance. The locus-specific effects of the polygenes ranged from 0.002 to 0.15%, with effect sizes selected from negative exponential distributions. All polygenes act independently and have additive effects. Individuals in the LDL upper tail were designated medicated. Subjects medicated increased across visits at 2%, 5%, and 15%. Coronary artery calcification (CAC) was simulated using age, lipid levels, and CAC-specific polymorphisms. The risk of myocardial infarction before each visit was determined by CAC and its interactions with smoking and two genetic loci. Smoking was simulated to be commensurate with rates reported by the Centers for Disease Control. Two hundred replications were simulated.

WDTC1, the ortholog of Drosophila adipose gene, associates with human obesity, modulated by MUFA intake.

Abstract: Adipose (adp) is an obesity gene in Drosophila and mice with crucial functions in fat metabolism. We investigated the correlation between genetic variation of the WDTC1 locus, the ortholog of adp, and human obesity. Five WDTC1 single-nucleotide polymorphisms (SNPs) were genotyped in 935 and 1,115 adults of two ethnically diverse US populations. In the Boston Puerto Rican population, we demonstrated that two WDTC1 SNPs strongly associated with obesity. Homozygote and heterozygote carriers of the major allele i22835A, representing ∼96% of the population, had significantly higher mean BMI (31.5 and 31.0 kg/m2, respectively) than noncarriers (28.6 kg/m2). Conversely, homozygotes of the minor allele i22835G were leaner and were 74% less likely to be overweight or obese (odds ratio (OR) = 0.26, P = 0.003) compared to homozygote carriers of the major allele. Haplotype analyses based on two SNPs further supported these findings. In addition, we found a strong interaction of monounsaturated fatty acid (MUFA) intake by genotype in this population. As dietary MUFA intake increased, minor allele carriers of SNP i22835A>G had higher BMIs, whereas major allele carriers had lower BMIs. A white population also exhibited a pattern of association between WDTC1 genotypes and obesity although of a different nature. Those WDTC1 variants which associated with obesity likely have experienced strong positive selection in human history, when food supply was unpredictable. Given the high frequency of the major alleles in both populations, we suggest that WDTC1 variation may be an important risk factor contributing to obesity in these populations.

Longitudinal trends in the association of metabolic syndrome with 550 k single-nucleotide polymorphisms in the Framingham Heart Study

Abstract: We investigated the association of metabolic syndrome (MetS) with a 500 k and a 50 k single-nucleotide polymorphism (SNP) gene chip in the Framingham Heart Study. We cross-sectionally evaluated the MetS longitudinal trends. Data analyzed were from the Offspring Cohort (four exams: first (n = 2,441), third (n = 2,185), fifth (n = 2,308), and seventh (n = 2,328)) and the Generation 3 Cohort (one exam: the first exam (n = 3,997)). The prevalence of MetS was determined using the National Cholesterol Education Program Adult Treatment Panel III diagnostic criteria, modified with a newly developed correction for medication use. The association test between an SNP and MetS was performed with a generalized estimating equations method under the additive genetic model. Multiple-testing corrections were also performed. The prevalence of MetS in the offspring cohort increased from one visit to the next, and reached the highest point by the seventh exam comparable with the prevalence reported for the general US population. The pattern of the MetS prevalence over time also reflected itself in the association tests, in which the highest significances were seen in the fifth and seventh exams. The association tests showed that SNPs within genes PRDM16, CETP, PTHB1, PAPPA, and FBN3, and also some SNPs not in genes were significant or close to significance at the genome-wide thresholds. These findings are important in terms of eventually identifying with the causal loci for MetS.

Multiple genes influence BMI on chromosome 7q31-34: the NHLBI Family Heart Study.

Abstract: The National Heart, Lung, and Blood Institute Family Heart Study (FHS) genome-wide linkage scan identified a region of chromosome 7q31-34 with a lod score of 4.9 for BMI at D7S1804 (131.9 Mb). We report the results of linkage and association to BMI in this region for two independent FHS samples. The first sample includes 225 FHS pedigrees with evidence of linkage to 7q31-34, using 1,132 single-nucleotide polymorphisms (SNPs) and 7 microsatellites. The second represents a case-control sample (318 cases; BMI >25 and 325 controls; BMI <25) derived from unrelated FHS participants who were not part of the genome scan. The latter set was genotyped for 606 SNPs, including 37 SNPs with prior evidence for association in the linked families. Although variance components linkage analysis using only SNPs generated a peak lod score that coincided with the original linkage scan at 131.9 Mb, a conditional linkage analysis showed evidence of a second quantitative trait locus (QTL) near 143 cM influencing BMI. Three SNPs (rs161339, rs12673281, and rs1993068) located near the three genes pleiotrophin (PTN), diacylglycerol (DAG) kinase iota (DGK iota), and cholinergic receptor, muscarinic 2 (CHRM2) demonstrated significant association in both linked families (P = 0.0005, 0.002, and 0.03, respectively) and the case-control sample (P = 0.01, 0.0003, and 0.03, respectively), regardless of the genetic model tested. These findings suggest that several genes may be associated with BMI in the 7q31-34 region.

Association of thymidylate synthase variants with 5-fluorouracil cytotoxicity.

Abstract: Identifying relevant cytotoxicity genes using an ex-vivo lymphoblastoid cell line (LCLs) model has distinct advantages for pharmacogenomic discovery studies of cancer chemotherapy, including standardized treatment conditions, availability of large numbers of samples, and publicly available genotypic data. However, there is little proof of principal data to confirm the promise of this approach. One of the known targets of 5-fluorouracil (5-FU) treatment is thymidylate synthase (TYMS). We hypothesized that genetic variants in TYMS would alter cytotoxicity because of 5-FU treatment using a LCL model system. LCLs from the Centre d'Etude du Polymorphisme Humain (CEPH) pedigrees (N=427) were treated with eight concentrations of 5-FU for 72 h, and cytotoxicity was determined using an Alamar Blue assay. For a subset of the 30 International Haplotype Mapping project (HapMap) trios, genotype data for 46 single-nucleotide polymorphism (SNP) variants encompassing the TYMS gene were downloaded from the HapMap website. Using a mixed models approach, each SNP was tested for association to 5-FU cytotoxicity in the subset of HapMap trios. Putatively associated SNPs (P<0.01), were then genotyped in the remaining LCLs in the CEPH pedigrees and tested for association. Two intronic SNPs in TYMS (rs2847153 and rs2853533) were significantly associated (P<0.01) with 5-FU cytotoxicity in the HapMap subset using the mixed models approach. After genotyping these SNPs in the full CEPH pedigrees, the associations with cytotoxicity showed a more reliable significance (P<0.0005), as a result of the increase in sample size. These results highlight the importance of the TYMS gene variants in response to 5-FU treatment. Furthermore, they provide additional biological validation of the relevance of LCLs as a model for pharmacogenomic gene discovery in cancer chemotherapy.

The challenge of detecting epistasis (G x G interactions): Genetic Analysis Workshop 16.

Abstract: Interest is increasing in epistasis as a possible source of the unexplained variance missed by genome-wide association studies. The Genetic Analysis Workshop 16 Group 9 participants evaluated a wide variety of classical and novel analytical methods for detecting epistasis, in both the statistical and machine learning paradigms, applied to both real and simulated data. Because the magnitude of epistasis is clearly relative to scale of penetrance, and therefore to some extent, to the choice of model framework, it is not surprising that strong interactions under one model might be minimized or even disappear entirely under a different modeling framework.

Genetic Variants at the PDZ-Interacting Domain of the Scavenger Receptor Class B Type I Interact with Diet to Influence the Risk of Metabolic Syndrome in Obese Men and Women

Abstract: The scaffolding protein PDZ domain containing 1 (PDZK1) regulates the HDL receptor scavenger receptor class B type I. However, the effect of PDZK1 genetic variants on lipids and metabolic syndrome (MetS) traits remains unknown. This study evaluated the association of 3 PDZK1 single nucleotide polymorphisms (SNP) (i33968C > T, i15371G > A, and i19738C > T) with lipids and risk of MetS and their potential interactions with diet. PDZK1 SNP were genotyped in 1000 participants (481 men, 519 women) included in the Genetics of Lipid Lowering Drugs and Diet Network study. Lipoprotein subfractions were measured by proton NMR spectroscopy and dietary intake was estimated using a validated questionnaire. The PDZK1_i33968C > T polymorphism was associated with MetS (P = 0.034), mainly driven by the association of the minor T allele with higher plasma triglycerides (P = 0.004) and VLDL (P = 0.021), and lower adiponectin concentrations (P = 0.022) than in participants homozygous for the major allele (C). We found a significant gene x BMI x diet interaction, in which the deleterious association of the i33968T allele with MetS was observed in obese participants with high PUFA and carbohydrate (P-values ranging from 0.004 to 0.020) intakes. Conversely, a there was a protective effect in nonobese participants with high PUFA intake (P T genetic variants may be associated with a higher risk of exhibiting MetS. This gene x BMI x diet interaction offers the potential to identify dietary and other lifestyle changes that may obviate the onset of MetS in individuals with a specific genetic background.

Epistatic interactions of CDKN2B-TCF7L2 for risk of type 2 diabetes and of CDKN2B-JAZF1 for triglyceride/high-density lipoprotein ratio longitudinal change: evidence from the Framingham Heart Study

Abstract: Fifteen known type 2 diabetes (T2D) gene variants were assessed for their associations with T2D status in 228 T2D families from the Framingham Heart Study (FHS) Original, Offspring, and Children Cohorts. Bayesian approach was used to test single-single-nucleotide polymorphism (SNP) association followed by logistic regression. Bayesian and logic regression approaches were used to test multiple SNP association searching for the best combinations of variants followed by logistic regression reconfirmation. The significant variants for T2D risk were also tested for their main and interacting effects on triglyceride (TG)/high-density lipoprotein (HDL) ratio change derived from four point measures across time. This slope phenotype was made available using mixed model growth curve approach from 155 T2D families in the FHS Offspring Cohort.

A QTL on 12q Influencing an Inflammation Marker and Obesity in White Women: The NHLBI Family Heart Study

Abstract: It has been recognized that obese individuals are intrinsically in a state of chronic inflammation, as indicated by positive correlations between serum levels of C-reactive protein (CRP) and various anthropometric measures of obesity. To explore the hypothesis that a gene(s) may underlie this relationship, we conducted bivariate linkage analyses of BMI and CRP in white and African-American (AA) families of the National Heart, Lung, and Blood Institute (NHLBI) Family Heart Study (FHS). Variance components linkage analysis as implemented in SOLAR was performed in 1,825 whites (840 men and 985 women) and 548 AAs (199 men and 351 women). CRP exhibited significant genetic correlations with BMI in women (0.54 ± 0.10 for white and 0.53 ± 0.14 for AA) and the combined samples (0.37 ± 0.09 for white and 0.56 ± 0.13 for AA), but not in men. We detected a maximum bivariate lod score of 3.86 on chromosome 12q24.2–24.3 at 139 cM and a suggestive linkage signal (lod = 2.19) on chromosome 19p13.1 (44 cM) in white women. Both bivariate peaks were substantially higher than their respective univariate lods at the same locus for each trait. No significant lod scores were detected in AAs. Our results indicate that chromosome 12q may harbor quantitative trait loci (QTLs) jointly regulating BMI and CRP in white women.

Genetic Analysis Workshop 16: Strategies for genome-wide association study analyses

Abstract: National Institutes of Health (AR44422, N01-AR-7-2232); Genome Canada and Associations AFP; Polyarctique-Groupe Taitbout; Rhumatisme et Travail; Arthritis Research Campaign; National Institute of General Medical Sciences (R01 GM31575)

A framework for analyzing both linkage and association: An analysis of Genetic Analysis Workshop 16 simulated data

Abstract: We examine a Bayesian Markov-chain Monte Carlo framework for simultaneous segregation and linkage analysis in the simulated single-nucleotide polymorphism data provided for Genetic Analysis Workshop 16. We conducted linkage only, linkage and association, and association only tests under this framework. We also compared these results with variance-component linkage analysis and regression analyses. The results indicate that the method shows some promise, but finding genes that have very small (<0.1%) contributions to trait variance may require additional sources of information. All methods examined fared poorly for the smallest in the simulated "polygene" range (h2 of 0.0015 to 0.0002).

Polyunsaturated Fatty Acids Modulate the Effect of TCF7L2 Gene Variants on

Abstract: The transcription factor 7-like 2 (TCF7L2) has been recently associated with diabetes risk, and it may exert its effect through metabolic syndrome (MetS)-related traits and be subjected to modification by environmental factors. We investigated the effect of single nucleotide polymorphisms (SNP), rs7903146 and rs12255372, within the TCF7L2 locus on postprandial lipemia and other MetS-related traits and their modulation by dietary fat. Data were collected from 1083 European Americans participating in the Genetics of Lipid Lowering Drugs and Diet Network Study. Carriers of the minor T allele at the C/T rs7903146 SNP had higher fasting plasma glucose (P ¼ 0.012), lower homeostasis model assessment of b cell function (P ¼ 0.041), higher plasma VLDL (P ¼ 0.035), and lower large LDL particle (P ¼ 0.007) concentrations and higher risk of MetS (P ¼ 0.011) than CC individuals. Moreover, we identified significant interactions between this SNP and PUFA intake modulating fasting VLDL particle concentrations (P ¼ 0.016) and postprandial triglycerides (TG) (P ¼ 0.028), chylomicrons (P ¼ 0.025), total VLDL (P ¼ 0.026), and large VLDL (P ¼ 0.018) concentrations. Thus, only T allele carriers with a PUFA intake $7.36% of energy had elevated fasting plasma VLDL concentrations and postprandial TG-rich lipoproteins. These variables did not differ in T allele carriers and noncarriers in the low-PUFA intake group. Moreover, these significant interactions were due exclusively to (n-6) PUFA intake. In summary, high (n-6) PUFA intakes ($6.62% of energy intake) were associated with atherogenic dyslipidemia in carriers of the minor T allele at the TCF7L2 rs7903146