International journal of cancer. Journal international du cancer, Jan 5, 2015
Prostate cancer (PC) has the highest degree of genetic transmission of any form of malignancy. In... more Prostate cancer (PC) has the highest degree of genetic transmission of any form of malignancy. In some families, the hereditary pattern is so strong as to mimic an autosomal dominance trait. We reviewed the known predisposing genetic markers to assess possible strategies for screening of families at risk. We carried out a systematic literature search using the Pubmed service of the National Center for Biotechnology Information (NCBI) and several gene libraries, including the NCBI SNP Library, the Online Mendelian Inheritance in Man® Catalog of Human Genes and Genetic Disorders (OMIM) and SNPedia to obtain known gene loci, SNPs and satellite markers associated with PC. We further cross referenced information on identified loci comparing data from different articles and gene reference sites. Whenever possible, we recorded the odds ratio (OR) for the allele associated with PC. In multiple different linkage studies, many independent PC associated loci have been identified on separate ch...
Sleep duration is implicated in the etiologies of chronic diseases and premature mortality. Howev... more Sleep duration is implicated in the etiologies of chronic diseases and premature mortality. However, the genetic basis for sleep duration is poorly defined. We sought to identify novel genetic components influencing sleep duration in a multi-ethnic sample.Meta-analyses were conducted of genetic associations with self-reported, habitual sleep duration from 7 Candidate Gene Association Resource (CARe) cohorts of over 25,000 individuals of African-, Asian-, European-, and Hispanic-American ancestry. All individuals were genotyped for ∼50,000 SNPs from 2,000 candidate heart, lung, blood and sleep genes. African-Americans had additional genome-wide genotypes. Four cohorts provided replication.A SNP (rs17601612) in the dopamine D2 receptor gene (DRD2) was significantly associated with sleep duration (p=9.8 x 10(-7)). Conditional analysis identified a second DRD2 signal with opposite effects on sleep duration. In exploratory analysis, suggestive association was observed for rs17601612 with...
Gallbladder disease (GBD) has an overall prevalence of 10-40% depending on factors such as age, g... more Gallbladder disease (GBD) has an overall prevalence of 10-40% depending on factors such as age, gender, population, obesity and diabetes, and represents a major economic burden. Although gallstones are composed of cholesterol by-products and are associated with obesity, presumed causal pathways remain unproven, although BMI reduction is typically recommended. We performed genetic studies to discover candidate genes and define pathways involved in GBD. We genotyped 15 241 women of European ancestry from three cohorts, including 3216 with GBD, using the Human cardiovascular disease (HumanCVD) BeadChip containing up to ~53 000 single-nucleotide polymorphisms (SNPs). Effect sizes with P-values for development of GBD were generated. We identify two new loci associated with GBD, GCKR rs1260326:T>C (P=5.88 × 10(-7), ß=-0.146) and TTC39B rs686030:C>A (P=6.95x10(-7), ß=0.271) and detect four independent SNP effects in ABCG8…
Background Clustering of cardiovascular (CV) risks believed to contribute to the rising burden of... more Background Clustering of cardiovascular (CV) risks believed to contribute to the rising burden of debilitating and life-threatening disorders, the increasing rates of obesity and type 2 diabetes, and the growing importance of metabolic syndrome, have made assessment of CV risk clustering an urgent undertaking. Though these diseases often cluster in individuals and families, the basis of their aggregation is not well known. Objective: This study was designed to understand the pathogenesis of Syndrome X and determine what independent factors can be extracted to better fit and explain the total variance of obesity, diabetes, hypertension and Syndrome X among African Americans. Methods Exploratory factor analysis (principal components analysis) was performed with data from 5301 African-American participants in the Jackson Heart Study (JHS)using the Factor procedure in SAS. Measured variables included sex, age at Exam 1,fasting triglyceride level, total cholesterol, LDL cholesterol, fast...
The aim of this study was to test for evidence of Mendelian segregation of a major gene in the Ja... more The aim of this study was to test for evidence of Mendelian segregation of a major gene in the Jackson Heart Study (JHS), a large African American cohort, and to develop models for future use in model-based linkage analysis. The QT interval, measured in electrocardiograms has been shown to be heritable, with an estimate of 41% in the Jackson Heart Study. Using data from the same cohort, a segregation analysis of the QT interval was conducted. A Box-Cox transformation was applied while simultaneously estimating the parameters of the model using the SEGREG program in the S.A.G.E 6.1.0 package. An environmental model with two means fitted the data better than an environmental model with one mean. The most parsimonious genetic model that best fitted the data was a codominant model with an allele frequency of 0.19, providing suggestive evidence of Mendelian segregation of a major gene underlying this trait. There was no significant residual spousal correlation in the environmental or gen...
The identification and exploration of genetic loci that influence smoking behaviors have been con... more The identification and exploration of genetic loci that influence smoking behaviors have been conducted primarily in populations of the European ancestry. Here we report results of the first genome-wide association study meta-analysis of smoking behavior in African Americans in the Study of Tobacco in Minority Populations Genetics Consortium (n = 32,389). We identified one non-coding single-nucleotide polymorphism (SNP; rs2036527[A]) on chromosome 15q25.1 associated with smoking quantity (cigarettes per day), which exceeded genome-wide significance (β = 0.040, s.e. = 0.007, P = 1.84 × 10(-8)). This variant is present in the 5'-distal enhancer region of the CHRNA5 gene and defines the primary index signal reported in studies of the European ancestry. No other SNP reached genome-wide significance for smoking initiation (SI, ever vs never smoking), age of SI, or smoking cessation (SC, former vs current smoking). Informative associations that approached genome-wide significance incl...
When a cancer predisposing germline mutation is detected in an index case, the presence of the un... more When a cancer predisposing germline mutation is detected in an index case, the presence of the underlying syndrome is confirmed and the potential for predictive testing of at-risk relatives is established. However, the reporting of a positive family history does not routinely lead to communication of information about risk to close, much less distant relatives. This review summarizes information technology utilized to address penetration or 'reach' of knowledge of risk within extended families, including the use of telephone and video counseling to reach distant patients, and anticipate novel internet-based processes for communication between investigators and relatives.
Ethnic differences in cardiac arrhythmia incidence have been reported, with a particularly high i... more Ethnic differences in cardiac arrhythmia incidence have been reported, with a particularly high incidence of sudden cardiac death and low incidence of atrial fibrillation in individuals of African ancestry. We tested the hypotheses that African ancestry and common genetic variants are associated with prolonged duration of cardiac repolarization, a central pathophysiological determinant of arrhythmia, as measured by the electrocardiographic QT interval. First, individual estimates of African and European ancestry were inferred from genome-wide single-nucleotide polymorphism (SNP) data in 7 population-based cohorts of African Americans (n=12,097) and regressed on measured QT interval from ECGs. Second, imputation was performed for 2.8 million SNPs, and a genome-wide association study of QT interval was performed in 10 cohorts (n=13,105). There was no evidence of association between genetic ancestry and QT interval (P=0.94). Genome-wide significant associations (P<2.5 × 10(-8)) were identified with SNPs at 2 loci, upstream of the genes NOS1AP (rs12143842, P=2 × 10(-15)) and ATP1B1 (rs1320976, P=2 × 10(-10)). The most significant SNP in NOS1AP was the same as the strongest SNP previously associated with QT interval in individuals of European ancestry. Low probability values…
Endothelial function is abnormal in chronic obstructive pulmonary disease (COPD); whether endothe... more Endothelial function is abnormal in chronic obstructive pulmonary disease (COPD); whether endothelial dysfunction causes COPD is unknown. Test associations of endothelial biomarkers with FEV1 using instrumental variables. Among 26 907 participants with spirometry, ICAM-1, P-selectin, E-selectin and endothelin-1 were measured in subsets. ICAM-1 and P-selectin were inversely associated with FEV1 among European-Americans (-29 mL and -34 mL per standard deviation of log-transformed biomarker, p < 0.001), as was endothelin-1 among African-Americans (-22 mL, p = 0.008). Genetically-estimated ICAM-1 and P-selectin were not significantly associated with FEV1. The instrumental variable for endothelin-1 was non-informative. Although ICAM-1, P-selectin and endothelin-1 were inversely associated with FEV1, associations for ICAM-1 and P-selectin do not appear causal.
To identify genetic factors contributing to type 2 diabetes (T2D), we performed large-scale meta-... more To identify genetic factors contributing to type 2 diabetes (T2D), we performed large-scale meta-analyses by using a custom??? 50,000 SNP genotyping array (the ITMAT-Broad-CARe array) with??? 2000 candidate genes in 39 multiethnic population-based studies, case-...
Advances in next-generation sequencing technology have enabled systematic exploration of the cont... more Advances in next-generation sequencing technology have enabled systematic exploration of the contribution of rare variation to Mendelian and complex diseases. Although it is well known that population stratification can generate spurious associations with common alleles, its impact on rare variant association methods remains poorly understood. Here, we performed exhaustive coalescent simulations with demographic parameters calibrated from exome sequence data to evaluate the performance of nine rare variant association methods in the presence of fine-scale population structure. We find that all methods have an inflated spurious association rate for parameter values that are consistent with levels of differentiation typical of European populations. For example, at a nominal significance level of 5%, some test statistics have a spurious association rate as high as 40%. Finally, we empirically assess the impact of population stratification in a large data set of 4,298 European American exomes. Our results have important implications for the design, analysis, and interpretation of rare variant genome-wide association studies.
International journal of cancer. Journal international du cancer, Jan 5, 2015
Prostate cancer (PC) has the highest degree of genetic transmission of any form of malignancy. In... more Prostate cancer (PC) has the highest degree of genetic transmission of any form of malignancy. In some families, the hereditary pattern is so strong as to mimic an autosomal dominance trait. We reviewed the known predisposing genetic markers to assess possible strategies for screening of families at risk. We carried out a systematic literature search using the Pubmed service of the National Center for Biotechnology Information (NCBI) and several gene libraries, including the NCBI SNP Library, the Online Mendelian Inheritance in Man® Catalog of Human Genes and Genetic Disorders (OMIM) and SNPedia to obtain known gene loci, SNPs and satellite markers associated with PC. We further cross referenced information on identified loci comparing data from different articles and gene reference sites. Whenever possible, we recorded the odds ratio (OR) for the allele associated with PC. In multiple different linkage studies, many independent PC associated loci have been identified on separate ch...
Sleep duration is implicated in the etiologies of chronic diseases and premature mortality. Howev... more Sleep duration is implicated in the etiologies of chronic diseases and premature mortality. However, the genetic basis for sleep duration is poorly defined. We sought to identify novel genetic components influencing sleep duration in a multi-ethnic sample.Meta-analyses were conducted of genetic associations with self-reported, habitual sleep duration from 7 Candidate Gene Association Resource (CARe) cohorts of over 25,000 individuals of African-, Asian-, European-, and Hispanic-American ancestry. All individuals were genotyped for ∼50,000 SNPs from 2,000 candidate heart, lung, blood and sleep genes. African-Americans had additional genome-wide genotypes. Four cohorts provided replication.A SNP (rs17601612) in the dopamine D2 receptor gene (DRD2) was significantly associated with sleep duration (p=9.8 x 10(-7)). Conditional analysis identified a second DRD2 signal with opposite effects on sleep duration. In exploratory analysis, suggestive association was observed for rs17601612 with...
Gallbladder disease (GBD) has an overall prevalence of 10-40% depending on factors such as age, g... more Gallbladder disease (GBD) has an overall prevalence of 10-40% depending on factors such as age, gender, population, obesity and diabetes, and represents a major economic burden. Although gallstones are composed of cholesterol by-products and are associated with obesity, presumed causal pathways remain unproven, although BMI reduction is typically recommended. We performed genetic studies to discover candidate genes and define pathways involved in GBD. We genotyped 15 241 women of European ancestry from three cohorts, including 3216 with GBD, using the Human cardiovascular disease (HumanCVD) BeadChip containing up to ~53 000 single-nucleotide polymorphisms (SNPs). Effect sizes with P-values for development of GBD were generated. We identify two new loci associated with GBD, GCKR rs1260326:T>C (P=5.88 × 10(-7), ß=-0.146) and TTC39B rs686030:C>A (P=6.95x10(-7), ß=0.271) and detect four independent SNP effects in ABCG8…
Background Clustering of cardiovascular (CV) risks believed to contribute to the rising burden of... more Background Clustering of cardiovascular (CV) risks believed to contribute to the rising burden of debilitating and life-threatening disorders, the increasing rates of obesity and type 2 diabetes, and the growing importance of metabolic syndrome, have made assessment of CV risk clustering an urgent undertaking. Though these diseases often cluster in individuals and families, the basis of their aggregation is not well known. Objective: This study was designed to understand the pathogenesis of Syndrome X and determine what independent factors can be extracted to better fit and explain the total variance of obesity, diabetes, hypertension and Syndrome X among African Americans. Methods Exploratory factor analysis (principal components analysis) was performed with data from 5301 African-American participants in the Jackson Heart Study (JHS)using the Factor procedure in SAS. Measured variables included sex, age at Exam 1,fasting triglyceride level, total cholesterol, LDL cholesterol, fast...
The aim of this study was to test for evidence of Mendelian segregation of a major gene in the Ja... more The aim of this study was to test for evidence of Mendelian segregation of a major gene in the Jackson Heart Study (JHS), a large African American cohort, and to develop models for future use in model-based linkage analysis. The QT interval, measured in electrocardiograms has been shown to be heritable, with an estimate of 41% in the Jackson Heart Study. Using data from the same cohort, a segregation analysis of the QT interval was conducted. A Box-Cox transformation was applied while simultaneously estimating the parameters of the model using the SEGREG program in the S.A.G.E 6.1.0 package. An environmental model with two means fitted the data better than an environmental model with one mean. The most parsimonious genetic model that best fitted the data was a codominant model with an allele frequency of 0.19, providing suggestive evidence of Mendelian segregation of a major gene underlying this trait. There was no significant residual spousal correlation in the environmental or gen...
The identification and exploration of genetic loci that influence smoking behaviors have been con... more The identification and exploration of genetic loci that influence smoking behaviors have been conducted primarily in populations of the European ancestry. Here we report results of the first genome-wide association study meta-analysis of smoking behavior in African Americans in the Study of Tobacco in Minority Populations Genetics Consortium (n = 32,389). We identified one non-coding single-nucleotide polymorphism (SNP; rs2036527[A]) on chromosome 15q25.1 associated with smoking quantity (cigarettes per day), which exceeded genome-wide significance (β = 0.040, s.e. = 0.007, P = 1.84 × 10(-8)). This variant is present in the 5'-distal enhancer region of the CHRNA5 gene and defines the primary index signal reported in studies of the European ancestry. No other SNP reached genome-wide significance for smoking initiation (SI, ever vs never smoking), age of SI, or smoking cessation (SC, former vs current smoking). Informative associations that approached genome-wide significance incl...
When a cancer predisposing germline mutation is detected in an index case, the presence of the un... more When a cancer predisposing germline mutation is detected in an index case, the presence of the underlying syndrome is confirmed and the potential for predictive testing of at-risk relatives is established. However, the reporting of a positive family history does not routinely lead to communication of information about risk to close, much less distant relatives. This review summarizes information technology utilized to address penetration or 'reach' of knowledge of risk within extended families, including the use of telephone and video counseling to reach distant patients, and anticipate novel internet-based processes for communication between investigators and relatives.
Ethnic differences in cardiac arrhythmia incidence have been reported, with a particularly high i... more Ethnic differences in cardiac arrhythmia incidence have been reported, with a particularly high incidence of sudden cardiac death and low incidence of atrial fibrillation in individuals of African ancestry. We tested the hypotheses that African ancestry and common genetic variants are associated with prolonged duration of cardiac repolarization, a central pathophysiological determinant of arrhythmia, as measured by the electrocardiographic QT interval. First, individual estimates of African and European ancestry were inferred from genome-wide single-nucleotide polymorphism (SNP) data in 7 population-based cohorts of African Americans (n=12,097) and regressed on measured QT interval from ECGs. Second, imputation was performed for 2.8 million SNPs, and a genome-wide association study of QT interval was performed in 10 cohorts (n=13,105). There was no evidence of association between genetic ancestry and QT interval (P=0.94). Genome-wide significant associations (P<2.5 × 10(-8)) were identified with SNPs at 2 loci, upstream of the genes NOS1AP (rs12143842, P=2 × 10(-15)) and ATP1B1 (rs1320976, P=2 × 10(-10)). The most significant SNP in NOS1AP was the same as the strongest SNP previously associated with QT interval in individuals of European ancestry. Low probability values…
Endothelial function is abnormal in chronic obstructive pulmonary disease (COPD); whether endothe... more Endothelial function is abnormal in chronic obstructive pulmonary disease (COPD); whether endothelial dysfunction causes COPD is unknown. Test associations of endothelial biomarkers with FEV1 using instrumental variables. Among 26 907 participants with spirometry, ICAM-1, P-selectin, E-selectin and endothelin-1 were measured in subsets. ICAM-1 and P-selectin were inversely associated with FEV1 among European-Americans (-29 mL and -34 mL per standard deviation of log-transformed biomarker, p < 0.001), as was endothelin-1 among African-Americans (-22 mL, p = 0.008). Genetically-estimated ICAM-1 and P-selectin were not significantly associated with FEV1. The instrumental variable for endothelin-1 was non-informative. Although ICAM-1, P-selectin and endothelin-1 were inversely associated with FEV1, associations for ICAM-1 and P-selectin do not appear causal.
To identify genetic factors contributing to type 2 diabetes (T2D), we performed large-scale meta-... more To identify genetic factors contributing to type 2 diabetes (T2D), we performed large-scale meta-analyses by using a custom??? 50,000 SNP genotyping array (the ITMAT-Broad-CARe array) with??? 2000 candidate genes in 39 multiethnic population-based studies, case-...
Advances in next-generation sequencing technology have enabled systematic exploration of the cont... more Advances in next-generation sequencing technology have enabled systematic exploration of the contribution of rare variation to Mendelian and complex diseases. Although it is well known that population stratification can generate spurious associations with common alleles, its impact on rare variant association methods remains poorly understood. Here, we performed exhaustive coalescent simulations with demographic parameters calibrated from exome sequence data to evaluate the performance of nine rare variant association methods in the presence of fine-scale population structure. We find that all methods have an inflated spurious association rate for parameter values that are consistent with levels of differentiation typical of European populations. For example, at a nominal significance level of 5%, some test statistics have a spurious association rate as high as 40%. Finally, we empirically assess the impact of population stratification in a large data set of 4,298 European American exomes. Our results have important implications for the design, analysis, and interpretation of rare variant genome-wide association studies.
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Papers by Sarah Buxbaum