Dongbing Lai - Academia.edu (original) (raw)

Papers by Dongbing Lai

Research paper thumbnail of Charcot-Marie-Tooth gene, SBF2, associated with taxane-induced peripheral neuropathy in African Americans

Oncotarget, 2015

Taxane-induced peripheral neuropathy (TIPN) is one of the most important survivorship issues for ... more Taxane-induced peripheral neuropathy (TIPN) is one of the most important survivorship issues for cancer patients. African Americans (AA) have previously been shown to have an increased risk for this toxicity. Germline predictive biomarkers were evaluated to help identify a priori which patients might be at extraordinarily high risk for this toxicity. Whole exome sequencing was performed using germline DNA from 213 AA patients who received a standard dose and schedule of paclitaxel in the adjuvant, randomized phase III breast cancer trial, E5103. Cases were defined as those with either grade 3-4 (n=64) or grade 2-4 (n=151) TIPN and were compared to controls (n=62) that were not reported to have experienced TIPN. We retained for analysis rare variants with a minor allele frequency <3% and which were predicted to be deleterious by protein prediction programs. A gene-based, case-control analysis using SKAT was performed to identify genes that harbored an imbalance of deleterious variants associated with increased risk of TIPN. Five genes had a p-value < 10-4 for grade 3-4 TIPN analysis and three genes had a p-value < 10-4 for the grade 2-4 TIPN analysis. For the grade 3-4 TIPN analysis, SET binding factor 2 (SBF2) was significantly associated with TIPN (p-value=4.35 x10-6). Five variants were predicted to be deleterious in SBF2. Inherited mutations in SBF2 have previously been associated with autosomal recessive, Type 4B2 Charcot-Marie-Tooth (CMT) disease. Rare variants in SBF2, a CMT gene, predict an increased risk of TIPN in AA patients receiving paclitaxel.

Research paper thumbnail of Polymorphisms in the Estrogen Receptor β (ESR2) Gene Are Associated with Bone Mineral Density in Caucasian Men and Women

The Journal of Clinical Endocrinology Metabolism, Jul 2, 2013

Research paper thumbnail of Association of Adenylate Cyclase 10 ( ADCY10 ) Polymorphisms and Bone Mineral Density in Healthy Adults

Calcified Tissue International, Feb 1, 2009

Phenotypic variation in bone mineral density (BMD) among healthy adults is influenced by both gen... more Phenotypic variation in bone mineral density (BMD) among healthy adults is influenced by both genetic and environmental factors. Genetic sequence variations in the adenylate cyclase 10 (ADCY10) gene, which is also called soluble adenylate cyclase, have previously been reported to be associated with low spinal BMD in hypercalciuric patients. Since ADCY10 is located in the region linked to spinal BMD in our previous linkage analysis, we tested whether polymorphisms in this gene are also associated with normal BMD variation in healthy adults. Sixteen single nucleotide polymorphisms (SNPs) distributed throughout ADCY10 were genotyped in two healthy groups of American whites: 1,692 premenopausal women and 715 men. Statistical analyses were performed in the two groups to test for association between these SNPs and femoral neck and lumbar spine areal BMD. We observed significant evidence of association (p<0.01) with one SNP each in men and women. Genotypes at these SNPs accounted for less than 1% of hip BMD variation in men, but 1.5% of spinal BMD in women. However, adjacent SNPs did not corroborate the association in either males or females. In conclusion, we found a modest association between an ADCY10 polymorphism and spinal areal BMD in premenopausal white women.

Research paper thumbnail of Shared Genetic Risk Factors of Intracranial, Abdominal, and Thoracic Aneurysms

Journal of the American Heart Association, Jan 14, 2016

Intracranial aneurysms (IAs), abdominal aortic aneurysms (AAAs), and thoracic aortic aneurysms (T... more Intracranial aneurysms (IAs), abdominal aortic aneurysms (AAAs), and thoracic aortic aneurysms (TAAs) all have a familial predisposition. Given that aneurysm types are known to co-occur, we hypothesized that there may be shared genetic risk factors for IAs, AAAs, and TAAs. We performed a mega-analysis of 1000 Genomes Project-imputed genome-wide association study (GWAS) data of 4 previously published aneurysm cohorts: 2 IA cohorts (in total 1516 cases, 4305 controls), 1 AAA cohort (818 cases, 3004 controls), and 1 TAA cohort (760 cases, 2212 controls), and observed associations of 4 known IA, AAA, and/or TAA risk loci (9p21, 18q11, 15q21, and 2q33) with consistent effect directions in all 4 cohorts. We calculated polygenic scores based on IA-, AAA-, and TAA-associated SNPs and tested these scores for association to case-control status in the other aneurysm cohorts; this revealed no shared polygenic effects. Similarly, linkage disequilibrium-score regression analyses did not show sign...

Research paper thumbnail of Sex-Specific and Non-Sex-Specific Quantitative Trait Loci Contribute to Normal Variation in Bone Mineral Density in Men

Introduction: A major determinant of osteoporotic fracture is peak bone mineral density (BMD). In... more Introduction: A major determinant of osteoporotic fracture is peak bone mineral density (BMD). In women peak BMD is highly heritable and several quantitative trait loci (QTL) have been reported. There are few comparable data in men. This study in men aimed to establish the heritability of peak BMD, identify QTL contributing to normal variation in BMD, and determine which QTL might be sex specific.

Research paper thumbnail of Genome Screen to Detect Linkage to Common Susceptibility Genes for Intracranial and Aortic Aneurysms

Background and Purpose-Risk for both intracranial aneurysms (IAs) and aortic aneurysms (AAs) is t... more Background and Purpose-Risk for both intracranial aneurysms (IAs) and aortic aneurysms (AAs) is thought to be heritable with mounting evidence for genetic predisposition. The concept of shared risk for these conditions is challenged by differences in age of diagnosis and demographic characteristics. We performed a genomewide linkage analysis in multiplex families with both IA and AA from the Familial Intracranial Aneurysm study. Methods-Available medical records of subjects who reported IA or abdominal/thoracic AA were reviewed with adjudication as definite/probable, possible, or not a case. To identify genes contributing to the susceptibility for IA and AA, genomewide linkage analysis was performed in the 26 multiplex IA families who had members who also had thoracic or abdominal AA. Individuals (nϭ91) were defined as affected if they had an IA (definite/probable) or an aortic or thoracic AA (definite/probable). Results-Maximum logarithm of odds (LOD) scores were found on chromosomes 11 (144 cM; LODϭ3.0) and 6 (33 cM;

Research paper thumbnail of Genome Screen to Detect Linkage to Intracranial Aneurysm Susceptibility Genes The Familial Intracranial Aneurysm (FIA) Study

Background and Purpose-Evidence supports a substantial genetic contribution to the risk of intrac... more Background and Purpose-Evidence supports a substantial genetic contribution to the risk of intracranial aneurysm (IA).

Research paper thumbnail of CLCN7 polymorphisms and bone mineral density in healthy premenopausal white women and in white men

Bone, Sep 1, 2008

Introduction-Mutations in the chloride channel 7 gene (CLCN7) cause osteopetrosis, and polymorphi... more Introduction-Mutations in the chloride channel 7 gene (CLCN7) cause osteopetrosis, and polymorphisms of CLCN7 in the non-disease allele are associated with penetrance of the autosomal dominant osteopetrosis (ADO) phenotype. Studies have also shown an association between CLCN7 polymorphisms and bone mineral density (BMD) in women. However, there is no study to date that has examined whether CLCN7 polymorphisms underlie normal variation of peak BMD in healthy premenopausal white women and in white men.

Research paper thumbnail of Genome-wide association study of serum iron phenotypes in premenopausal women of European descent

Blood Cells, Molecules, and Diseases, 2016

A genome-wide association study was performed on 1130 premenopausal women to detect common varian... more A genome-wide association study was performed on 1130 premenopausal women to detect common variants associated with three serum iron-related phenotypes. Total iron binding capacity was strongly associated (p=10(-14)) with variants in and near the TF gene (transferrin), the serum iron transporting protein, and with variants in HFE (p=4×10(-7)), which encodes the human hemochromatosis gene. Association was also detected between percent iron saturation (p=10(-8)) and variants in the chromosome 6 region containing both HFE and SLC17A2, which encodes a phosphate transport protein. No significant associations were detected with serum iron, but variants in HFE were suggestive (p=10(-6)). Our results corroborate prior studies in older subjects and demonstrate that the association of these genetic variants with iron phenotypes can be detected in premenopausal women.

Research paper thumbnail of Genome-wide association of plasma homocysteine in the indianapolis-ibadan dementia study cohort

Alzheimer's & Dementia, 2015

Research paper thumbnail of Whole-Exome Sequencing in Familial Parkinson Disease

JAMA neurology, Jan 23, 2015

Parkinson disease (PD) is a progressive neurodegenerative disease for which susceptibility is lin... more Parkinson disease (PD) is a progressive neurodegenerative disease for which susceptibility is linked to genetic and environmental risk factors. To identify genetic variants contributing to disease risk in familial PD. A 2-stage study design that included a discovery cohort of families with PD and a replication cohort of familial probands was used. In the discovery cohort, rare exonic variants that segregated in multiple affected individuals in a family and were predicted to be conserved or damaging were retained. Genes with retained variants were prioritized if expressed in the brain and located within PD-relevant pathways. Genes in which prioritized variants were observed in at least 4 families were selected as candidate genes for replication in the replication cohort. The setting was among individuals with familial PD enrolled from academic movement disorder specialty clinics across the United States. All participants had a family history of PD. Identification of genes containing ...

Research paper thumbnail of Genetic Influences on Plasma Homocysteine Levels in African Americans and Yoruba Nigerians

Journal of Alzheimer's disease : JAD, Jan 30, 2015

Plasma homocysteine, a metabolite involved in key cellular methylation processes seems to be impl... more Plasma homocysteine, a metabolite involved in key cellular methylation processes seems to be implicated in cognitive functions and cardiovascular health with its high levels representing a potential modifiable risk factor for Alzheimer's disease (AD) and other dementias. A better understanding of the genetic factors regulating homocysteine levels, particularly in non-white populations, may help in risk stratification analyses of existing clinical trials and may point to novel targets for homocysteine-lowering therapy. To identify genetic influences on plasma homocysteine levels in individuals with African ancestry, we performed a targeted gene and pathway-based analysis using a priori biological information and then to identify new association performed a genome-wide association study. All analyses used combined data from the African American and Yoruba cohorts from the Indianapolis-Ibadan Dementia Project. Targeted analyses demonstrated significant associations of homocysteine ...

Research paper thumbnail of Genome-wide association studies for taxane-induced peripheral neuropathy (TIPN) in ECOG-5103 and ECOG-1199

Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 2, 2015

Purpose Taxane induced peripheral neuropathy (TIPN) is an important survivorship issue for many c... more Purpose Taxane induced peripheral neuropathy (TIPN) is an important survivorship issue for many cancer patients. Currently, there are no clinically implemented biomarkers to predict which patients might be at increased risk for TIPN. We present a comprehensive approach to identification of genetic variants to predict TIPN. Experimental Design We performed a genome wide association study (GWAS) in 3431 patients from the phase III adjuvant breast cancer trial, ECOG-5103 to compare genotypes with TIPN. We performed candidate validation of top SNPs for TIPN in another phase III adjuvant breast cancer trial, ECOG-1199. Results When evaluating for Grade 3-4 TIPN, 120 SNPs had a p-value <10-4 from patients of European descent (EA) in ECOG-5103. 30 candidate SNPs were subsequently tested in ECOG-1199 and SNP rs3125923 was found to be significantly associated with Grade 3-4 TIPN (p=1.7x10-3; OR=1.8). Race was also a major predictor of TIPN, with patients of African descent (AA) experienci...

Research paper thumbnail of Polymorphisms in the Estrogen Receptor (ESR2) Gene Are Associated with Bone Mineral Density in Caucasian Men and Women

Research paper thumbnail of Lessons Learned from Whole Exome Sequencing in Multiplex Families Affected by a Complex Genetic Disorder, Intracranial Aneurysm

Research paper thumbnail of Genetic variant predicts bevacizumab-induced hypertension in ECOG-5103 and ECOG-2100

British Journal of Cancer, 2014

Background: Bevacizumab has broad anti-tumour activity, but substantial risk of hypertension. No ... more Background: Bevacizumab has broad anti-tumour activity, but substantial risk of hypertension. No reliable markers are available for predicting bevacizumab-induced hypertension.

Research paper thumbnail of Genome Screen to Detect Linkage to Intracranial Aneurysm Susceptibility Genes: The Familial Intracranial Aneurysm (FIA) Study

Stroke, 2008

Background and Purpose-Evidence supports a substantial genetic contribution to the risk of intrac... more Background and Purpose-Evidence supports a substantial genetic contribution to the risk of intracranial aneurysm (IA).

Research paper thumbnail of The Relationship Between Smoking and Replicated Sequence Variants on Chromosomes 8 and 9 With Familial Intracranial Aneurysm

Stroke, 2010

Purpose-To replicate the previous association of single nucleotide polymorphisms (SNPs) with risk... more Purpose-To replicate the previous association of single nucleotide polymorphisms (SNPs) with risk of intracranial aneurysm (IA) and to examine the relationship of smoking with these variants and the risk of IA.

Research paper thumbnail of Genome Screen to Detect Linkage to Common Susceptibility Genes for Intracranial and Aortic Aneurysms

Stroke, 2009

Background and Purpose-Risk for both intracranial aneurysms (IAs) and aortic aneurysms (AAs) is t... more Background and Purpose-Risk for both intracranial aneurysms (IAs) and aortic aneurysms (AAs) is thought to be heritable with mounting evidence for genetic predisposition. The concept of shared risk for these conditions is challenged by differences in age of diagnosis and demographic characteristics. We performed a genomewide linkage analysis in multiplex families with both IA and AA from the Familial Intracranial Aneurysm study. Methods-Available medical records of subjects who reported IA or abdominal/thoracic AA were reviewed with adjudication as definite/probable, possible, or not a case. To identify genes contributing to the susceptibility for IA and AA, genomewide linkage analysis was performed in the 26 multiplex IA families who had members who also had thoracic or abdominal AA. Individuals (nϭ91) were defined as affected if they had an IA (definite/probable) or an aortic or thoracic AA (definite/probable). Results-Maximum logarithm of odds (LOD) scores were found on chromosomes 11 (144 cM; LODϭ3.0) and 6 (33 cM;

Research paper thumbnail of Polymorphisms in the bone morphogenetic protein 2 (BMP2) gene do not affect bone mineral density in white men or women

Osteoporosis International, 2006

Introduction: Peak bone mineral density (BMD) achieved during adulthood is a major determinant of... more Introduction: Peak bone mineral density (BMD) achieved during adulthood is a major determinant of osteoporotic fracture in later life. Although environmental factors affect peak BMD, it is a highly heritable trait. Recently, bone morphogenetic protein 2 (BMP2) was reported as a susceptibility gene for osteoporotic fractures and low BMD in Icelandic and Danish populations. Methods: To determine whether polymorphisms in the BMP2 gene contribute to BMD variation in our population of healthy American whites, we tested seven single nucleotide polymorphisms (SNPs), four of which were associated with osteoporotic phenotypes in the previous study. BMD at the femoral neck and lumbar spine (L2-L4) were measured by dual energy X-ray absorptiometry (DXA) in 411 men (age 18-61) and 1,291 pre-menopausal women (age 20-50). SNP genotypes/ haplotypes were tested for population-based association with BMD using analysis of variance. Results: None of the polymorphisms tested reached statistical significance (all p values >0.05) for BMD at the femoral neck or lumbar spine in either gender. Two of the SNP haplotypes spanning the entire BMP2 gene were marginally associated with BMD in men (p values=0.019−0.043). However, these haplotypes would account for only a small, if any, portion of BMD variation and would not be significant after adjustment for multiple comparisons. Conclusions: These results demonstrate that genetic variations in BMP2 do not substantially contribute to BMD variation in our population of healthy American whites.

Research paper thumbnail of Charcot-Marie-Tooth gene, SBF2, associated with taxane-induced peripheral neuropathy in African Americans

Oncotarget, 2015

Taxane-induced peripheral neuropathy (TIPN) is one of the most important survivorship issues for ... more Taxane-induced peripheral neuropathy (TIPN) is one of the most important survivorship issues for cancer patients. African Americans (AA) have previously been shown to have an increased risk for this toxicity. Germline predictive biomarkers were evaluated to help identify a priori which patients might be at extraordinarily high risk for this toxicity. Whole exome sequencing was performed using germline DNA from 213 AA patients who received a standard dose and schedule of paclitaxel in the adjuvant, randomized phase III breast cancer trial, E5103. Cases were defined as those with either grade 3-4 (n=64) or grade 2-4 (n=151) TIPN and were compared to controls (n=62) that were not reported to have experienced TIPN. We retained for analysis rare variants with a minor allele frequency &amp;amp;amp;amp;lt;3% and which were predicted to be deleterious by protein prediction programs. A gene-based, case-control analysis using SKAT was performed to identify genes that harbored an imbalance of deleterious variants associated with increased risk of TIPN. Five genes had a p-value &amp;amp;amp;amp;lt; 10-4 for grade 3-4 TIPN analysis and three genes had a p-value &amp;amp;amp;amp;lt; 10-4 for the grade 2-4 TIPN analysis. For the grade 3-4 TIPN analysis, SET binding factor 2 (SBF2) was significantly associated with TIPN (p-value=4.35 x10-6). Five variants were predicted to be deleterious in SBF2. Inherited mutations in SBF2 have previously been associated with autosomal recessive, Type 4B2 Charcot-Marie-Tooth (CMT) disease. Rare variants in SBF2, a CMT gene, predict an increased risk of TIPN in AA patients receiving paclitaxel.

Research paper thumbnail of Polymorphisms in the Estrogen Receptor β (ESR2) Gene Are Associated with Bone Mineral Density in Caucasian Men and Women

The Journal of Clinical Endocrinology Metabolism, Jul 2, 2013

Research paper thumbnail of Association of Adenylate Cyclase 10 ( ADCY10 ) Polymorphisms and Bone Mineral Density in Healthy Adults

Calcified Tissue International, Feb 1, 2009

Phenotypic variation in bone mineral density (BMD) among healthy adults is influenced by both gen... more Phenotypic variation in bone mineral density (BMD) among healthy adults is influenced by both genetic and environmental factors. Genetic sequence variations in the adenylate cyclase 10 (ADCY10) gene, which is also called soluble adenylate cyclase, have previously been reported to be associated with low spinal BMD in hypercalciuric patients. Since ADCY10 is located in the region linked to spinal BMD in our previous linkage analysis, we tested whether polymorphisms in this gene are also associated with normal BMD variation in healthy adults. Sixteen single nucleotide polymorphisms (SNPs) distributed throughout ADCY10 were genotyped in two healthy groups of American whites: 1,692 premenopausal women and 715 men. Statistical analyses were performed in the two groups to test for association between these SNPs and femoral neck and lumbar spine areal BMD. We observed significant evidence of association (p<0.01) with one SNP each in men and women. Genotypes at these SNPs accounted for less than 1% of hip BMD variation in men, but 1.5% of spinal BMD in women. However, adjacent SNPs did not corroborate the association in either males or females. In conclusion, we found a modest association between an ADCY10 polymorphism and spinal areal BMD in premenopausal white women.

Research paper thumbnail of Shared Genetic Risk Factors of Intracranial, Abdominal, and Thoracic Aneurysms

Journal of the American Heart Association, Jan 14, 2016

Intracranial aneurysms (IAs), abdominal aortic aneurysms (AAAs), and thoracic aortic aneurysms (T... more Intracranial aneurysms (IAs), abdominal aortic aneurysms (AAAs), and thoracic aortic aneurysms (TAAs) all have a familial predisposition. Given that aneurysm types are known to co-occur, we hypothesized that there may be shared genetic risk factors for IAs, AAAs, and TAAs. We performed a mega-analysis of 1000 Genomes Project-imputed genome-wide association study (GWAS) data of 4 previously published aneurysm cohorts: 2 IA cohorts (in total 1516 cases, 4305 controls), 1 AAA cohort (818 cases, 3004 controls), and 1 TAA cohort (760 cases, 2212 controls), and observed associations of 4 known IA, AAA, and/or TAA risk loci (9p21, 18q11, 15q21, and 2q33) with consistent effect directions in all 4 cohorts. We calculated polygenic scores based on IA-, AAA-, and TAA-associated SNPs and tested these scores for association to case-control status in the other aneurysm cohorts; this revealed no shared polygenic effects. Similarly, linkage disequilibrium-score regression analyses did not show sign...

Research paper thumbnail of Sex-Specific and Non-Sex-Specific Quantitative Trait Loci Contribute to Normal Variation in Bone Mineral Density in Men

Introduction: A major determinant of osteoporotic fracture is peak bone mineral density (BMD). In... more Introduction: A major determinant of osteoporotic fracture is peak bone mineral density (BMD). In women peak BMD is highly heritable and several quantitative trait loci (QTL) have been reported. There are few comparable data in men. This study in men aimed to establish the heritability of peak BMD, identify QTL contributing to normal variation in BMD, and determine which QTL might be sex specific.

Research paper thumbnail of Genome Screen to Detect Linkage to Common Susceptibility Genes for Intracranial and Aortic Aneurysms

Background and Purpose-Risk for both intracranial aneurysms (IAs) and aortic aneurysms (AAs) is t... more Background and Purpose-Risk for both intracranial aneurysms (IAs) and aortic aneurysms (AAs) is thought to be heritable with mounting evidence for genetic predisposition. The concept of shared risk for these conditions is challenged by differences in age of diagnosis and demographic characteristics. We performed a genomewide linkage analysis in multiplex families with both IA and AA from the Familial Intracranial Aneurysm study. Methods-Available medical records of subjects who reported IA or abdominal/thoracic AA were reviewed with adjudication as definite/probable, possible, or not a case. To identify genes contributing to the susceptibility for IA and AA, genomewide linkage analysis was performed in the 26 multiplex IA families who had members who also had thoracic or abdominal AA. Individuals (nϭ91) were defined as affected if they had an IA (definite/probable) or an aortic or thoracic AA (definite/probable). Results-Maximum logarithm of odds (LOD) scores were found on chromosomes 11 (144 cM; LODϭ3.0) and 6 (33 cM;

Research paper thumbnail of Genome Screen to Detect Linkage to Intracranial Aneurysm Susceptibility Genes The Familial Intracranial Aneurysm (FIA) Study

Background and Purpose-Evidence supports a substantial genetic contribution to the risk of intrac... more Background and Purpose-Evidence supports a substantial genetic contribution to the risk of intracranial aneurysm (IA).

Research paper thumbnail of CLCN7 polymorphisms and bone mineral density in healthy premenopausal white women and in white men

Bone, Sep 1, 2008

Introduction-Mutations in the chloride channel 7 gene (CLCN7) cause osteopetrosis, and polymorphi... more Introduction-Mutations in the chloride channel 7 gene (CLCN7) cause osteopetrosis, and polymorphisms of CLCN7 in the non-disease allele are associated with penetrance of the autosomal dominant osteopetrosis (ADO) phenotype. Studies have also shown an association between CLCN7 polymorphisms and bone mineral density (BMD) in women. However, there is no study to date that has examined whether CLCN7 polymorphisms underlie normal variation of peak BMD in healthy premenopausal white women and in white men.

Research paper thumbnail of Genome-wide association study of serum iron phenotypes in premenopausal women of European descent

Blood Cells, Molecules, and Diseases, 2016

A genome-wide association study was performed on 1130 premenopausal women to detect common varian... more A genome-wide association study was performed on 1130 premenopausal women to detect common variants associated with three serum iron-related phenotypes. Total iron binding capacity was strongly associated (p=10(-14)) with variants in and near the TF gene (transferrin), the serum iron transporting protein, and with variants in HFE (p=4×10(-7)), which encodes the human hemochromatosis gene. Association was also detected between percent iron saturation (p=10(-8)) and variants in the chromosome 6 region containing both HFE and SLC17A2, which encodes a phosphate transport protein. No significant associations were detected with serum iron, but variants in HFE were suggestive (p=10(-6)). Our results corroborate prior studies in older subjects and demonstrate that the association of these genetic variants with iron phenotypes can be detected in premenopausal women.

Research paper thumbnail of Genome-wide association of plasma homocysteine in the indianapolis-ibadan dementia study cohort

Alzheimer's & Dementia, 2015

Research paper thumbnail of Whole-Exome Sequencing in Familial Parkinson Disease

JAMA neurology, Jan 23, 2015

Parkinson disease (PD) is a progressive neurodegenerative disease for which susceptibility is lin... more Parkinson disease (PD) is a progressive neurodegenerative disease for which susceptibility is linked to genetic and environmental risk factors. To identify genetic variants contributing to disease risk in familial PD. A 2-stage study design that included a discovery cohort of families with PD and a replication cohort of familial probands was used. In the discovery cohort, rare exonic variants that segregated in multiple affected individuals in a family and were predicted to be conserved or damaging were retained. Genes with retained variants were prioritized if expressed in the brain and located within PD-relevant pathways. Genes in which prioritized variants were observed in at least 4 families were selected as candidate genes for replication in the replication cohort. The setting was among individuals with familial PD enrolled from academic movement disorder specialty clinics across the United States. All participants had a family history of PD. Identification of genes containing ...

Research paper thumbnail of Genetic Influences on Plasma Homocysteine Levels in African Americans and Yoruba Nigerians

Journal of Alzheimer's disease : JAD, Jan 30, 2015

Plasma homocysteine, a metabolite involved in key cellular methylation processes seems to be impl... more Plasma homocysteine, a metabolite involved in key cellular methylation processes seems to be implicated in cognitive functions and cardiovascular health with its high levels representing a potential modifiable risk factor for Alzheimer's disease (AD) and other dementias. A better understanding of the genetic factors regulating homocysteine levels, particularly in non-white populations, may help in risk stratification analyses of existing clinical trials and may point to novel targets for homocysteine-lowering therapy. To identify genetic influences on plasma homocysteine levels in individuals with African ancestry, we performed a targeted gene and pathway-based analysis using a priori biological information and then to identify new association performed a genome-wide association study. All analyses used combined data from the African American and Yoruba cohorts from the Indianapolis-Ibadan Dementia Project. Targeted analyses demonstrated significant associations of homocysteine ...

Research paper thumbnail of Genome-wide association studies for taxane-induced peripheral neuropathy (TIPN) in ECOG-5103 and ECOG-1199

Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 2, 2015

Purpose Taxane induced peripheral neuropathy (TIPN) is an important survivorship issue for many c... more Purpose Taxane induced peripheral neuropathy (TIPN) is an important survivorship issue for many cancer patients. Currently, there are no clinically implemented biomarkers to predict which patients might be at increased risk for TIPN. We present a comprehensive approach to identification of genetic variants to predict TIPN. Experimental Design We performed a genome wide association study (GWAS) in 3431 patients from the phase III adjuvant breast cancer trial, ECOG-5103 to compare genotypes with TIPN. We performed candidate validation of top SNPs for TIPN in another phase III adjuvant breast cancer trial, ECOG-1199. Results When evaluating for Grade 3-4 TIPN, 120 SNPs had a p-value <10-4 from patients of European descent (EA) in ECOG-5103. 30 candidate SNPs were subsequently tested in ECOG-1199 and SNP rs3125923 was found to be significantly associated with Grade 3-4 TIPN (p=1.7x10-3; OR=1.8). Race was also a major predictor of TIPN, with patients of African descent (AA) experienci...

Research paper thumbnail of Polymorphisms in the Estrogen Receptor (ESR2) Gene Are Associated with Bone Mineral Density in Caucasian Men and Women

Research paper thumbnail of Lessons Learned from Whole Exome Sequencing in Multiplex Families Affected by a Complex Genetic Disorder, Intracranial Aneurysm

Research paper thumbnail of Genetic variant predicts bevacizumab-induced hypertension in ECOG-5103 and ECOG-2100

British Journal of Cancer, 2014

Background: Bevacizumab has broad anti-tumour activity, but substantial risk of hypertension. No ... more Background: Bevacizumab has broad anti-tumour activity, but substantial risk of hypertension. No reliable markers are available for predicting bevacizumab-induced hypertension.

Research paper thumbnail of Genome Screen to Detect Linkage to Intracranial Aneurysm Susceptibility Genes: The Familial Intracranial Aneurysm (FIA) Study

Stroke, 2008

Background and Purpose-Evidence supports a substantial genetic contribution to the risk of intrac... more Background and Purpose-Evidence supports a substantial genetic contribution to the risk of intracranial aneurysm (IA).

Research paper thumbnail of The Relationship Between Smoking and Replicated Sequence Variants on Chromosomes 8 and 9 With Familial Intracranial Aneurysm

Stroke, 2010

Purpose-To replicate the previous association of single nucleotide polymorphisms (SNPs) with risk... more Purpose-To replicate the previous association of single nucleotide polymorphisms (SNPs) with risk of intracranial aneurysm (IA) and to examine the relationship of smoking with these variants and the risk of IA.

Research paper thumbnail of Genome Screen to Detect Linkage to Common Susceptibility Genes for Intracranial and Aortic Aneurysms

Stroke, 2009

Background and Purpose-Risk for both intracranial aneurysms (IAs) and aortic aneurysms (AAs) is t... more Background and Purpose-Risk for both intracranial aneurysms (IAs) and aortic aneurysms (AAs) is thought to be heritable with mounting evidence for genetic predisposition. The concept of shared risk for these conditions is challenged by differences in age of diagnosis and demographic characteristics. We performed a genomewide linkage analysis in multiplex families with both IA and AA from the Familial Intracranial Aneurysm study. Methods-Available medical records of subjects who reported IA or abdominal/thoracic AA were reviewed with adjudication as definite/probable, possible, or not a case. To identify genes contributing to the susceptibility for IA and AA, genomewide linkage analysis was performed in the 26 multiplex IA families who had members who also had thoracic or abdominal AA. Individuals (nϭ91) were defined as affected if they had an IA (definite/probable) or an aortic or thoracic AA (definite/probable). Results-Maximum logarithm of odds (LOD) scores were found on chromosomes 11 (144 cM; LODϭ3.0) and 6 (33 cM;

Research paper thumbnail of Polymorphisms in the bone morphogenetic protein 2 (BMP2) gene do not affect bone mineral density in white men or women

Osteoporosis International, 2006

Introduction: Peak bone mineral density (BMD) achieved during adulthood is a major determinant of... more Introduction: Peak bone mineral density (BMD) achieved during adulthood is a major determinant of osteoporotic fracture in later life. Although environmental factors affect peak BMD, it is a highly heritable trait. Recently, bone morphogenetic protein 2 (BMP2) was reported as a susceptibility gene for osteoporotic fractures and low BMD in Icelandic and Danish populations. Methods: To determine whether polymorphisms in the BMP2 gene contribute to BMD variation in our population of healthy American whites, we tested seven single nucleotide polymorphisms (SNPs), four of which were associated with osteoporotic phenotypes in the previous study. BMD at the femoral neck and lumbar spine (L2-L4) were measured by dual energy X-ray absorptiometry (DXA) in 411 men (age 18-61) and 1,291 pre-menopausal women (age 20-50). SNP genotypes/ haplotypes were tested for population-based association with BMD using analysis of variance. Results: None of the polymorphisms tested reached statistical significance (all p values >0.05) for BMD at the femoral neck or lumbar spine in either gender. Two of the SNP haplotypes spanning the entire BMP2 gene were marginally associated with BMD in men (p values=0.019−0.043). However, these haplotypes would account for only a small, if any, portion of BMD variation and would not be significant after adjustment for multiple comparisons. Conclusions: These results demonstrate that genetic variations in BMP2 do not substantially contribute to BMD variation in our population of healthy American whites.