Population substructure can lead to confounding in tests for genetic association, and failure to ... more Population substructure can lead to confounding in tests for genetic association, and failure to adjust properly can result in spurious findings. Here we address this issue of confounding by considering the impact of global ancestry (average ancestry across the genome) and local ancestry (ancestry at a specific chromosomal location) on regression parameters and relative power in ancestry-adjusted and -unadjusted models. We examine theoretical expectations under different scenarios for population substructure; applying different regression models, verifying and generalizing using simulations, and exploring the findings in real-world admixed populations. We show that admixture does not lead to confounding when the trait locus is tested directly in a single admixed population. However, if there is more complex population structure or a marker locus in linkage disequilibrium (LD) with the trait locus is tested, both global and local ancestry can be confounders. Additionally, we show the...
Several lines of evidence suggest that genetic factors and environmental exposures play a role in... more Several lines of evidence suggest that genetic factors and environmental exposures play a role in the development of pulmonary fibrosis. We evaluated families with 2 or more cases of idiopathic interstitial pneumonia among first-degree family members (familial interstitial pneumonia, or FIP), and identified 111 families with FIP having 309 affected and 360 unaffected individuals. The presence of probable or definite FIP was based on medical record review in 28 cases (9.1%); clinical history, diffusing capacity of carbon monoxide (DL(CO)), and chest X-ray in 16 cases (5.2%); clinical history, DL(CO), and high-resolution computed tomography chest scan in 191 cases (61.8%); clinical history and surgical lung biopsy in 56 cases (18.1%); and clinical history and autopsy in 18 cases (5.8%). Older age (68.3 vs. 53.1; p < 0.0001), male sex (55.7 vs. 37.2%; p < 0.0001), and having ever smoked cigarettes (67.3 vs. 34.1%; p…
Background: There has been increasing speculation that oxidative stress and abnormal energy metab... more Background: There has been increasing speculation that oxidative stress and abnormal energy metabolism may play a role in ASD (Autism Spectrum Disorders). It is essential that we begin to thoroughly identify and characterize the role of genes involved in oxidative stress, both those that reside in the mitochondria and those that are encoded in the nuclear genome. Of note there has been a profound lack of investigation into the role of mitochondrial variation in autism, despite numerous clinical reports describing patients with mitochondrial disorders or mutations who have symptoms consistent with ASD. Further, mitochondrial inheritance would be consistent with the observed increase in neuropsychological abnormalities in the mothers of ASD children. Objectives: To comprehensively examine the role of mitochondrial variation and nuclear-encoded mitochondrial gene variation with regard to autistic risk. Methods: We have resequenced a discovery dataset of ~200 Caucasian proband-father pa...
Autism spectrum disorder (ASD) is highly heritable, yet genome-wide association studies (GWAS), c... more Autism spectrum disorder (ASD) is highly heritable, yet genome-wide association studies (GWAS), copy number variation screens, and candidate gene association studies have found no single factor accounting for a large percentage of genetic risk. ASD trio exome sequencing studies have revealed genes with recurrent de novo loss-of-function variants as strong risk factors, but there are relatively few recurrently affected genes while as many as 1000 genes are predicted to play a role. As such, it is critical to identify the remaining rare and low-frequency variants contributing to ASD. We have utilized an approach of prioritization of genes by GWAS and follow-up with massively parallel sequencing in a case-control cohort. Using a previously reported ASD noise reduction GWAS analyses, we prioritized 837 RefSeq genes for custom targeting and sequencing. We sequenced the coding regions of those genes in 2071 ASD cases and 904 controls of European white ancestry. We applied comprehensive an...
Background: Genome-wide association studies (GWAS) and exome sequencing have found no single comm... more Background: Genome-wide association studies (GWAS) and exome sequencing have found no single common or rare factor accounting for the genetic risk for autism spectrum disorders (ASD). This leads to the hypothesis that genetic variants in hundreds of genes and nongenic loci contribute to ASD. Identification of such rare risk variants by sequencing large cohorts for rare or low frequency variants with potential functional significance to ASD is essential. Objectives: To identify rare coding and noncoding ASD risk variants integrating GWAS association with custom targeted massively parallel sequencing of candidate regions. Methods: Candidate regions were chosen from GWAS Noise Reduction analyses of two autism datasets (Hussman et. al., 2011). We sequenced 17Mb on the Illumina HiSeq2000 utilizing a custom Agilent SureSelect probe-set targeting exons, UTRs, conserved intronic areas, and regulatory regions of 681 GWAS-NR associated genes and conserved regions in 694 associated intergenic ...
Background: Autism spectrum disorder (ASD) is a highly prevalent developmental disorder, affectin... more Background: Autism spectrum disorder (ASD) is a highly prevalent developmental disorder, affecting an estimated 1 in 88 individuals, and is associated with significant morbidity. Despite demonstrating high heritability estimates, only a small proportion of the genetic risk for ASD is explained. While previous research, including genome wide association studies, has focused on the effects of common variants, recent exome sequencing studies suggest that rare variants (RVs) contribute significantly to ASD risk. Objectives: To identify RVs associated with ASD using two approaches; 1. An agnostic approach testing all genes on the Exome Array for association with ASD 2. A candidate gene approach testing ~1,000 genes previously implicated in ASD for association with ASD, including 254 genes previously reported as associated with ASD in a gene-based analysis using whole exome sequencing data. Methods: Participants were drawn from a large, family-based study of ASD and included 995 unrelated...
Association studies suggest that the G20210A mutation (G to A substitution at nucleotide position... more Association studies suggest that the G20210A mutation (G to A substitution at nucleotide position 20210) in the prothrombin gene (PT) is associated with increased plasma prothrombin activity and with increased risk for venous thromboembolism. To test directly for linkage between this PT variant and plasma prothrombin activity we performed a family-based study. The G20210A genotypes and plasma prothrombin activity levels were determined in 435 individuals belonging to 22 extended Spanish families. The sample was composed of 388 homozygous (G/G) normal individuals and 43 heterozygote (G/A) and 4 homozygote (A/A) carriers for the G20210A mutation. The results of variance-component linkage analysis yielded a highly significant lod score of 3.6 (P = 2.4 x 10(-5)) between this mutation and a quantitative trait locus (QTL) that influences prothrombin activity. Importantly, a conditional linkage analysis that simultaneously accounted for association with the G20210A variant completely elimi...
We describe a protocol for making a new type of gradient gel, the Composite gradient gel, that wa... more We describe a protocol for making a new type of gradient gel, the Composite gradient gel, that was designed to resolve plasma lipoproteins using nondenaturing gradient gel electrophoresis. The new gel format allows analysis both of high density lipoproteins (HDLs) and low density lipoproteins (LDLs) on the same gel. The gel gave highly repeatable (r2 = 0.999) size estimates. We compared lipoprotein phenotypes determined from the new gradient gel with those obtained using specialized HDL and LDL gradient gels. The comparisons indicated that the Composite gel gave lipoprotein particle size estimates for HDLs and LDLs that were virtually identical to those obtained, respectively, from the specialized HDL and LDL gradient gels. We measured median diameters, which reflect the distributions of absorbance, for LDLs and for HDLs and found that the Composite gel gave lipoprotein size distributions that were virtually identical to those measured using the specialized LDL and HDL gels. Finally...
Old Order Amish, founded by a small number of Swiss immigrants, exist in culturally isolated comm... more Old Order Amish, founded by a small number of Swiss immigrants, exist in culturally isolated communities across rural North America. The consequences of genetic isolation and inbreeding within this group are evident by increased frequencies of many monogenic diseases and several complex disorders. Conversely, the prevalence of Alzheimer disease (AD), the most common form of dementia, is lower in the Amish than in the general American population. Since mitochondrial dysfunction has been proposed as an underlying cause of AD and a specific haplogroup was found to affect AD susceptibility in Caucasians, we investigated whether inherited mitochondrial haplogroups affect risk of developing AD dementia in Ohio and Indiana Amish communities. Ninety-five independent matrilines were observed across six large pedigrees and three small pedigrees then classified into seven major European haplogroups. Haplogroup T is the most frequent haplogroup represented overall in these maternal lines (35.4%...
We explored the genetic control of cholesterolemic responses to dietary cholesterol and fat in 57... more We explored the genetic control of cholesterolemic responses to dietary cholesterol and fat in 575 pedigreed baboons. We measured cholesterol in b-lipoproteins (low density lipoprotein cholesterol (LDLC)) in blood drawn from baboons while they were consuming a baseline (low in cholesterol and fat) diet, a high-saturated fat (lard) diet, and a high-cholesterol, high-saturated fat diet. In addition to baseline levels
Background: Autism spectrum disorders (ASDs) comprise a range of neurodevelopmental conditions of... more Background: Autism spectrum disorders (ASDs) comprise a range of neurodevelopmental conditions of varying severity, characterized by marked qualitative difficulties in social relatedness, communication, and behavior. Despite overwhelming evidence of high heritability, results from genetic studies to date show that ASD etiology is extremely heterogeneous and only a fraction of autism genes have been discovered. Methods: To help unravel this genetic complexity, we performed whole exome sequencing on 100 ASD individuals from 40 families with multiple distantly related affected individuals. All families contained a minimum of one pair of ASD cousins. Each individual was captured with the Agilent SureSelect Human All Exon kit, sequenced on the Illumina Hiseq 2000, and the resulting data processed and annotated with Burrows-Wheeler Aligner (BWA), Genome Analysis Toolkit (GATK), and SeattleSeq. Genotyping information on each family was utilized in order to determine genomic regions that were identical by descent (IBD). Variants identified by exome sequencing which occurred in IBD regions and present in all affected individuals within each family were then evaluated to determine which may potentially be disease related. Nucleotide alterations that were novel and rare (minor allele frequency, MAF, less than 0.05) and predicted to be detrimental, either by altering amino acids or splicing patterns, were prioritized. Results: We identified numerous potentially damaging, ASD associated risk variants in genes previously unrelated to autism. A subset of these genes has been implicated in other neurobehavioral disorders including depression (SLIT3), epilepsy (CLCN2, PRICKLE1), intellectual disability (AP4M1), schizophrenia (WDR60), and Tourette syndrome (OFCC1). Additional alterations were found in previously reported autism candidate genes, including three genes with alterations in multiple families (CEP290, CSMD1, FAT1, and STXBP5). Compiling a list of ASD candidate genes from the literature, we determined that variants occurred in ASD candidate genes 1.65 times more frequently than in random genes captured by exome sequencing (P = 8.55 × 10 -5 ).
Background and Purpose-Sex differences have been recognized in stroke risk; however, the sex-depe... more Background and Purpose-Sex differences have been recognized in stroke risk; however, the sex-dependent genetic contribution to stroke is unclear. We sought to examine the sex-dependent associations between genes involved in lipid metabolism and carotid atherosclerotic plaque, a subclinical precursor of stroke.
Background and Purpose-The genetic influence on carotid atherosclerotic plaque is mostly unknown.... more Background and Purpose-The genetic influence on carotid atherosclerotic plaque is mostly unknown. This study examines the association between carotid plaque and single nucleotide polymorphisms in selected genes implicated in inflammation and endothelial function. Methods-A total of 43 genes (197 single nucleotide polymorphisms) involved in inflammation and endothelial function were interrogated in 287 Dominicans from the Northern Manhattan Study (mean age, 64Ϯ7 years; 58% women) who had undergone high-resolution B-mode ultrasound for examination of carotid plaque. Using an additive genetic model, multiple logistic regression analyses were conducted, a within-gene haplotype analysis was performed, and interactions between genes were examined. Results were validated in an independent set of 301 Dominicans.
Atherosclerosis is a complex subclinical cardiovascular disorder with a substantial genetic compo... more Atherosclerosis is a complex subclinical cardiovascular disorder with a substantial genetic component. This study sought to identify genetic loci influencing carotid plaque in 2 independent samples. B-mode ultrasound was performed to determine the presence and area of carotid plaque. Variance components analysis was used to test for linkage using 383 autosomal microsatellite markers in 1308 subjects from 100 Dominican families. Multiple linear and logistic regression models were used to investigate the association between plaque traits and 18,904 single nucleotide polymorphisms under the 1-logarithm of odds unit down regions of linkage peaks in an independent community-based data set (N = 941, 41% Dominicans) from the Northern Manhattan Study. After adjustment for age, hypertension, diabetes mellitus, cigarette pack-years, body mass index, and waist-to-hip ratio, significant heritability was detected for plaque presence (h² = 0.50 ± 0.14, P < 0.0001) and plaque area (h²=0.17 ± 0.04, P < 0.0001). Quantitative and dichotomous trait linkage analyses obtained similar results and identified 4 regions with multipoint logarithm of odds scores ≥ 2.00 on 7q36, 11p15, 14q32, and 15q23. In the association analysis of the 4 linkage peaks, several single nucleotide polymorphisms in or near SOX6, FSD2, AP3S2, EFTUD1, and MYOD1 were associated with carotid plaque traits with a nominal P ≤ 0.0005 in the Northern Manhattan Study data set and with a P ≤ 0.01 in Northern Manhattan Study Dominican subset. Carotid plaque has considerable heritability and may be influenced by loci on chromosomes 11p15, 14q32, and 15q23. The SOX6 gene within the bone morphogenic protein pathway could be a candidate for carotid plaque. Larger independent studies are needed to validate these findings.
Background and Purpose-Homocysteine levels are determined by genetic and environmental factors. S... more Background and Purpose-Homocysteine levels are determined by genetic and environmental factors. Several studies have linked high plasma levels of total homocysteine to the increased risk of cardiovascular disease, stroke, and many other conditions. However, the exact mechanism of documented and novel total homocysteine quantitative trait loci to that risk is unknown.
Population substructure can lead to confounding in tests for genetic association, and failure to ... more Population substructure can lead to confounding in tests for genetic association, and failure to adjust properly can result in spurious findings. Here we address this issue of confounding by considering the impact of global ancestry (average ancestry across the genome) and local ancestry (ancestry at a specific chromosomal location) on regression parameters and relative power in ancestry-adjusted and -unadjusted models. We examine theoretical expectations under different scenarios for population substructure; applying different regression models, verifying and generalizing using simulations, and exploring the findings in real-world admixed populations. We show that admixture does not lead to confounding when the trait locus is tested directly in a single admixed population. However, if there is more complex population structure or a marker locus in linkage disequilibrium (LD) with the trait locus is tested, both global and local ancestry can be confounders. Additionally, we show the...
Several lines of evidence suggest that genetic factors and environmental exposures play a role in... more Several lines of evidence suggest that genetic factors and environmental exposures play a role in the development of pulmonary fibrosis. We evaluated families with 2 or more cases of idiopathic interstitial pneumonia among first-degree family members (familial interstitial pneumonia, or FIP), and identified 111 families with FIP having 309 affected and 360 unaffected individuals. The presence of probable or definite FIP was based on medical record review in 28 cases (9.1%); clinical history, diffusing capacity of carbon monoxide (DL(CO)), and chest X-ray in 16 cases (5.2%); clinical history, DL(CO), and high-resolution computed tomography chest scan in 191 cases (61.8%); clinical history and surgical lung biopsy in 56 cases (18.1%); and clinical history and autopsy in 18 cases (5.8%). Older age (68.3 vs. 53.1; p < 0.0001), male sex (55.7 vs. 37.2%; p < 0.0001), and having ever smoked cigarettes (67.3 vs. 34.1%; p…
Background: There has been increasing speculation that oxidative stress and abnormal energy metab... more Background: There has been increasing speculation that oxidative stress and abnormal energy metabolism may play a role in ASD (Autism Spectrum Disorders). It is essential that we begin to thoroughly identify and characterize the role of genes involved in oxidative stress, both those that reside in the mitochondria and those that are encoded in the nuclear genome. Of note there has been a profound lack of investigation into the role of mitochondrial variation in autism, despite numerous clinical reports describing patients with mitochondrial disorders or mutations who have symptoms consistent with ASD. Further, mitochondrial inheritance would be consistent with the observed increase in neuropsychological abnormalities in the mothers of ASD children. Objectives: To comprehensively examine the role of mitochondrial variation and nuclear-encoded mitochondrial gene variation with regard to autistic risk. Methods: We have resequenced a discovery dataset of ~200 Caucasian proband-father pa...
Autism spectrum disorder (ASD) is highly heritable, yet genome-wide association studies (GWAS), c... more Autism spectrum disorder (ASD) is highly heritable, yet genome-wide association studies (GWAS), copy number variation screens, and candidate gene association studies have found no single factor accounting for a large percentage of genetic risk. ASD trio exome sequencing studies have revealed genes with recurrent de novo loss-of-function variants as strong risk factors, but there are relatively few recurrently affected genes while as many as 1000 genes are predicted to play a role. As such, it is critical to identify the remaining rare and low-frequency variants contributing to ASD. We have utilized an approach of prioritization of genes by GWAS and follow-up with massively parallel sequencing in a case-control cohort. Using a previously reported ASD noise reduction GWAS analyses, we prioritized 837 RefSeq genes for custom targeting and sequencing. We sequenced the coding regions of those genes in 2071 ASD cases and 904 controls of European white ancestry. We applied comprehensive an...
Background: Genome-wide association studies (GWAS) and exome sequencing have found no single comm... more Background: Genome-wide association studies (GWAS) and exome sequencing have found no single common or rare factor accounting for the genetic risk for autism spectrum disorders (ASD). This leads to the hypothesis that genetic variants in hundreds of genes and nongenic loci contribute to ASD. Identification of such rare risk variants by sequencing large cohorts for rare or low frequency variants with potential functional significance to ASD is essential. Objectives: To identify rare coding and noncoding ASD risk variants integrating GWAS association with custom targeted massively parallel sequencing of candidate regions. Methods: Candidate regions were chosen from GWAS Noise Reduction analyses of two autism datasets (Hussman et. al., 2011). We sequenced 17Mb on the Illumina HiSeq2000 utilizing a custom Agilent SureSelect probe-set targeting exons, UTRs, conserved intronic areas, and regulatory regions of 681 GWAS-NR associated genes and conserved regions in 694 associated intergenic ...
Background: Autism spectrum disorder (ASD) is a highly prevalent developmental disorder, affectin... more Background: Autism spectrum disorder (ASD) is a highly prevalent developmental disorder, affecting an estimated 1 in 88 individuals, and is associated with significant morbidity. Despite demonstrating high heritability estimates, only a small proportion of the genetic risk for ASD is explained. While previous research, including genome wide association studies, has focused on the effects of common variants, recent exome sequencing studies suggest that rare variants (RVs) contribute significantly to ASD risk. Objectives: To identify RVs associated with ASD using two approaches; 1. An agnostic approach testing all genes on the Exome Array for association with ASD 2. A candidate gene approach testing ~1,000 genes previously implicated in ASD for association with ASD, including 254 genes previously reported as associated with ASD in a gene-based analysis using whole exome sequencing data. Methods: Participants were drawn from a large, family-based study of ASD and included 995 unrelated...
Association studies suggest that the G20210A mutation (G to A substitution at nucleotide position... more Association studies suggest that the G20210A mutation (G to A substitution at nucleotide position 20210) in the prothrombin gene (PT) is associated with increased plasma prothrombin activity and with increased risk for venous thromboembolism. To test directly for linkage between this PT variant and plasma prothrombin activity we performed a family-based study. The G20210A genotypes and plasma prothrombin activity levels were determined in 435 individuals belonging to 22 extended Spanish families. The sample was composed of 388 homozygous (G/G) normal individuals and 43 heterozygote (G/A) and 4 homozygote (A/A) carriers for the G20210A mutation. The results of variance-component linkage analysis yielded a highly significant lod score of 3.6 (P = 2.4 x 10(-5)) between this mutation and a quantitative trait locus (QTL) that influences prothrombin activity. Importantly, a conditional linkage analysis that simultaneously accounted for association with the G20210A variant completely elimi...
We describe a protocol for making a new type of gradient gel, the Composite gradient gel, that wa... more We describe a protocol for making a new type of gradient gel, the Composite gradient gel, that was designed to resolve plasma lipoproteins using nondenaturing gradient gel electrophoresis. The new gel format allows analysis both of high density lipoproteins (HDLs) and low density lipoproteins (LDLs) on the same gel. The gel gave highly repeatable (r2 = 0.999) size estimates. We compared lipoprotein phenotypes determined from the new gradient gel with those obtained using specialized HDL and LDL gradient gels. The comparisons indicated that the Composite gel gave lipoprotein particle size estimates for HDLs and LDLs that were virtually identical to those obtained, respectively, from the specialized HDL and LDL gradient gels. We measured median diameters, which reflect the distributions of absorbance, for LDLs and for HDLs and found that the Composite gel gave lipoprotein size distributions that were virtually identical to those measured using the specialized LDL and HDL gels. Finally...
Old Order Amish, founded by a small number of Swiss immigrants, exist in culturally isolated comm... more Old Order Amish, founded by a small number of Swiss immigrants, exist in culturally isolated communities across rural North America. The consequences of genetic isolation and inbreeding within this group are evident by increased frequencies of many monogenic diseases and several complex disorders. Conversely, the prevalence of Alzheimer disease (AD), the most common form of dementia, is lower in the Amish than in the general American population. Since mitochondrial dysfunction has been proposed as an underlying cause of AD and a specific haplogroup was found to affect AD susceptibility in Caucasians, we investigated whether inherited mitochondrial haplogroups affect risk of developing AD dementia in Ohio and Indiana Amish communities. Ninety-five independent matrilines were observed across six large pedigrees and three small pedigrees then classified into seven major European haplogroups. Haplogroup T is the most frequent haplogroup represented overall in these maternal lines (35.4%...
We explored the genetic control of cholesterolemic responses to dietary cholesterol and fat in 57... more We explored the genetic control of cholesterolemic responses to dietary cholesterol and fat in 575 pedigreed baboons. We measured cholesterol in b-lipoproteins (low density lipoprotein cholesterol (LDLC)) in blood drawn from baboons while they were consuming a baseline (low in cholesterol and fat) diet, a high-saturated fat (lard) diet, and a high-cholesterol, high-saturated fat diet. In addition to baseline levels
Background: Autism spectrum disorders (ASDs) comprise a range of neurodevelopmental conditions of... more Background: Autism spectrum disorders (ASDs) comprise a range of neurodevelopmental conditions of varying severity, characterized by marked qualitative difficulties in social relatedness, communication, and behavior. Despite overwhelming evidence of high heritability, results from genetic studies to date show that ASD etiology is extremely heterogeneous and only a fraction of autism genes have been discovered. Methods: To help unravel this genetic complexity, we performed whole exome sequencing on 100 ASD individuals from 40 families with multiple distantly related affected individuals. All families contained a minimum of one pair of ASD cousins. Each individual was captured with the Agilent SureSelect Human All Exon kit, sequenced on the Illumina Hiseq 2000, and the resulting data processed and annotated with Burrows-Wheeler Aligner (BWA), Genome Analysis Toolkit (GATK), and SeattleSeq. Genotyping information on each family was utilized in order to determine genomic regions that were identical by descent (IBD). Variants identified by exome sequencing which occurred in IBD regions and present in all affected individuals within each family were then evaluated to determine which may potentially be disease related. Nucleotide alterations that were novel and rare (minor allele frequency, MAF, less than 0.05) and predicted to be detrimental, either by altering amino acids or splicing patterns, were prioritized. Results: We identified numerous potentially damaging, ASD associated risk variants in genes previously unrelated to autism. A subset of these genes has been implicated in other neurobehavioral disorders including depression (SLIT3), epilepsy (CLCN2, PRICKLE1), intellectual disability (AP4M1), schizophrenia (WDR60), and Tourette syndrome (OFCC1). Additional alterations were found in previously reported autism candidate genes, including three genes with alterations in multiple families (CEP290, CSMD1, FAT1, and STXBP5). Compiling a list of ASD candidate genes from the literature, we determined that variants occurred in ASD candidate genes 1.65 times more frequently than in random genes captured by exome sequencing (P = 8.55 × 10 -5 ).
Background and Purpose-Sex differences have been recognized in stroke risk; however, the sex-depe... more Background and Purpose-Sex differences have been recognized in stroke risk; however, the sex-dependent genetic contribution to stroke is unclear. We sought to examine the sex-dependent associations between genes involved in lipid metabolism and carotid atherosclerotic plaque, a subclinical precursor of stroke.
Background and Purpose-The genetic influence on carotid atherosclerotic plaque is mostly unknown.... more Background and Purpose-The genetic influence on carotid atherosclerotic plaque is mostly unknown. This study examines the association between carotid plaque and single nucleotide polymorphisms in selected genes implicated in inflammation and endothelial function. Methods-A total of 43 genes (197 single nucleotide polymorphisms) involved in inflammation and endothelial function were interrogated in 287 Dominicans from the Northern Manhattan Study (mean age, 64Ϯ7 years; 58% women) who had undergone high-resolution B-mode ultrasound for examination of carotid plaque. Using an additive genetic model, multiple logistic regression analyses were conducted, a within-gene haplotype analysis was performed, and interactions between genes were examined. Results were validated in an independent set of 301 Dominicans.
Atherosclerosis is a complex subclinical cardiovascular disorder with a substantial genetic compo... more Atherosclerosis is a complex subclinical cardiovascular disorder with a substantial genetic component. This study sought to identify genetic loci influencing carotid plaque in 2 independent samples. B-mode ultrasound was performed to determine the presence and area of carotid plaque. Variance components analysis was used to test for linkage using 383 autosomal microsatellite markers in 1308 subjects from 100 Dominican families. Multiple linear and logistic regression models were used to investigate the association between plaque traits and 18,904 single nucleotide polymorphisms under the 1-logarithm of odds unit down regions of linkage peaks in an independent community-based data set (N = 941, 41% Dominicans) from the Northern Manhattan Study. After adjustment for age, hypertension, diabetes mellitus, cigarette pack-years, body mass index, and waist-to-hip ratio, significant heritability was detected for plaque presence (h² = 0.50 ± 0.14, P < 0.0001) and plaque area (h²=0.17 ± 0.04, P < 0.0001). Quantitative and dichotomous trait linkage analyses obtained similar results and identified 4 regions with multipoint logarithm of odds scores ≥ 2.00 on 7q36, 11p15, 14q32, and 15q23. In the association analysis of the 4 linkage peaks, several single nucleotide polymorphisms in or near SOX6, FSD2, AP3S2, EFTUD1, and MYOD1 were associated with carotid plaque traits with a nominal P ≤ 0.0005 in the Northern Manhattan Study data set and with a P ≤ 0.01 in Northern Manhattan Study Dominican subset. Carotid plaque has considerable heritability and may be influenced by loci on chromosomes 11p15, 14q32, and 15q23. The SOX6 gene within the bone morphogenic protein pathway could be a candidate for carotid plaque. Larger independent studies are needed to validate these findings.
Background and Purpose-Homocysteine levels are determined by genetic and environmental factors. S... more Background and Purpose-Homocysteine levels are determined by genetic and environmental factors. Several studies have linked high plasma levels of total homocysteine to the increased risk of cardiovascular disease, stroke, and many other conditions. However, the exact mechanism of documented and novel total homocysteine quantitative trait loci to that risk is unknown.
Uploads
Papers by Susan Slifer