Other search tools

About this data

The publication data currently available has been vetted by Vanderbilt faculty, staff, administrators and trainees. The data itself is retrieved directly from NCBI's PubMed and is automatically updated on a weekly basis to ensure accuracy and completeness.

If you have any questions or comments, please contact us.

Results: 1 to 10 of 36

Publication Record


Analysis of Whole Exome Sequencing with Cardiometabolic Traits Using Family-Based Linkage and Association in the IRAS Family Study.
Tabb KL, Hellwege JN, Palmer ND, Dimitrov L, Sajuthi S, Taylor KD, Ng MC, Hawkins GA, Chen YI, Brown WM, McWilliams D, Williams A, Lorenzo C, Norris JM, Long J, Rotter JI, Curran JE, Blangero J, Wagenknecht LE, Langefeld CD, Bowden DW
(2017) Ann Hum Genet 81: 49-58
MeSH Terms: Adiponectin, Adolescent, Adult, Aged, Aged, 80 and over, Atherosclerosis, Exome, Female, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Insulin Resistance, Lipids, Lod Score, Male, Middle Aged, Polymorphism, Single Nucleotide, Sequence Analysis, DNA, Young Adult
Show Abstract · Added April 10, 2018
Family-based methods are a potentially powerful tool to identify trait-defining genetic variants in extended families, particularly when used to complement conventional association analysis. We utilized two-point linkage analysis and single variant association analysis to evaluate whole exome sequencing (WES) data from 1205 Hispanic Americans (78 families) from the Insulin Resistance Atherosclerosis Family Study. WES identified 211,612 variants above the minor allele frequency threshold of ≥0.005. These variants were tested for linkage and/or association with 50 cardiometabolic traits after quality control checks. Two-point linkage analysis yielded 10,580,600 logarithm of the odds (LOD) scores with 1148 LOD scores ≥3, 183 LOD scores ≥4, and 29 LOD scores ≥5. The maximal novel LOD score was 5.50 for rs2289043:T>C, in UNC5C with subcutaneous adipose tissue volume. Association analysis identified 13 variants attaining genome-wide significance (P < 5 × 10 ), with the strongest association between rs651821:C>T in APOA5 and triglyceride levels (P  =  3.67 × 10 ). Overall, there was a 5.2-fold increase in the number of informative variants detected by WES compared to exome chip analysis in this population, nearly 30% of which were novel variants relative to the Database of Single Nucleotide Polymorphisms (dbSNP) build 138. Thus, integration of results from two-point linkage and single-variant association analysis from WES data enabled identification of novel signals potentially contributing to cardiometabolic traits.
© 2017 John Wiley & Sons Ltd/University College London.
0 Communities
2 Members
0 Resources
MeSH Terms
Genome-wide linkage and association analysis of cardiometabolic phenotypes in Hispanic Americans.
Hellwege JN, Palmer ND, Dimitrov L, Keaton JM, Tabb KL, Sajuthi S, Taylor KD, Ng MC, Speliotes EK, Hawkins GA, Long J, Ida Chen YD, Lorenzo C, Norris JM, Rotter JI, Langefeld CD, Wagenknecht LE, Bowden DW
(2017) J Hum Genet 62: 175-184
MeSH Terms: Adolescent, Adult, Aged, Aged, 80 and over, Diabetes Mellitus, Type 2, Female, Genetic Linkage, Genome-Wide Association Study, Genotype, Hispanic Americans, Humans, Insulin Resistance, Laminin, Lod Score, Male, Middle Aged, NFI Transcription Factors, Polymorphism, Single Nucleotide, Tumor Necrosis Factor-alpha, Young Adult
Show Abstract · Added March 3, 2020
Linkage studies of complex genetic diseases have been largely replaced by genome-wide association studies, due in part to limited success in complex trait discovery. However, recent interest in rare and low-frequency variants motivates re-examination of family-based methods. In this study, we investigated the performance of two-point linkage analysis for over 1.6 million single-nucleotide polymorphisms (SNPs) combined with single variant association analysis to identify high impact variants, which are both strongly linked and associated with cardiometabolic traits in up to 1414 Hispanics from the Insulin Resistance Atherosclerosis Family Study (IRASFS). Evaluation of all 50 phenotypes yielded 83 557 000 LOD (logarithm of the odds) scores, with 9214 LOD scores ⩾3.0, 845 ⩾4.0 and 89 ⩾5.0, with a maximal LOD score of 6.49 (rs12956744 in the LAMA1 gene for tumor necrosis factor-α (TNFα) receptor 2). Twenty-seven variants were associated with P<0.005 as well as having an LOD score >4, including variants in the NFIB gene under a linkage peak with TNFα receptor 2 levels on chromosome 9. Linkage regions of interest included a broad peak (31 Mb) on chromosome 1q with acute insulin response (max LOD=5.37). This region was previously documented with type 2 diabetes in family-based studies, providing support for the validity of these results. Overall, we have demonstrated the utility of two-point linkage and association in comprehensive genome-wide array-based SNP genotypes.
0 Communities
1 Members
0 Resources
MeSH Terms
Admixture mapping of serum vitamin D and parathyroid hormone concentrations in the African American-Diabetes Heart Study.
Palmer ND, Divers J, Lu L, Register TC, Carr JJ, Hicks PJ, Smith SC, Xu J, Judd SE, Irvin MR, Gutierrez OM, Bowden DW, Wagenknecht LE, Langefeld CD, Freedman BI
(2016) Bone 87: 71-7
MeSH Terms: African Americans, Demography, Diabetes Mellitus, Type 2, Female, Humans, Linkage Disequilibrium, Lod Score, Male, Middle Aged, Parathyroid Hormone, Polymorphism, Single Nucleotide, Vitamin D
Show Abstract · Added September 29, 2016
Vitamin D and intact parathyroid hormone (iPTH) concentrations differ between individuals of African and European descent and may play a role in observed racial differences in bone mineral density (BMD). These findings suggest that mapping by admixture linkage disequilibrium (MALD) may be informative for identifying genetic variants contributing to these ethnic disparities. Admixture mapping was performed for serum 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, vitamin D-binding protein (VDBP), bioavailable vitamin D, and iPTH concentrations and computed tomography measured thoracic and lumbar vertebral volumetric BMD in 552 unrelated African Americans with type 2 diabetes from the African American-Diabetes Heart Study. Genotyping was performed using a custom Illumina ancestry informative marker (AIM) panel. For each AIM, the probability of inheriting 0, 1, or 2 copies of a European-derived allele was determined. Non-parametric linkage analysis was performed by testing for association between each AIM using these probabilities among phenotypes, accounting for global ancestry, age, and gender. Fine-mapping of MALD peaks was facilitated by genome-wide association study (GWAS) data. VDBP levels were significantly linked in proximity to the protein coding locus (rs7689609, LOD=11.05). Two loci exhibited significant linkage signals for 1,25-dihydroxyvitamin D on 13q21.2 (rs1622710, LOD=3.20) and 12q13.2 (rs11171526, LOD=3.10). iPTH was significantly linked on 9q31.3 (rs7854368, LOD=3.14). Fine-mapping with GWAS data revealed significant known (rs7041 with VDBP, P=1.38×10(-82)) and novel (rs12741813 and rs10863774 with VDBP, P<6.43×10(-5)) loci with plausible biological roles. Admixture mapping in combination with fine-mapping has focused efforts to identify loci contributing to ethnic differences in vitamin D-related traits.
Copyright © 2016 Elsevier Inc. All rights reserved.
0 Communities
1 Members
0 Resources
12 MeSH Terms
Empirical characteristics of family-based linkage to a complex trait: the ADIPOQ region and adiponectin levels.
Hellwege JN, Palmer ND, Mark Brown W, Brown MW, Ziegler JT, Sandy An S, An SS, Guo X, Ida Chen YD, Chen IY, Taylor K, Hawkins GA, Ng MC, Speliotes EK, Lorenzo C, Norris JM, Rotter JI, Wagenknecht LE, Langefeld CD, Bowden DW
(2015) Hum Genet 134: 203-13
MeSH Terms: Adiponectin, Adolescent, Adult, Aged, Aged, 80 and over, Databases, Nucleic Acid, Datasets as Topic, Family, Female, Genetic Linkage, Genetic Loci, Hispanic Americans, Humans, Lod Score, Male, Microsatellite Repeats, Middle Aged, Polymorphism, Single Nucleotide
Show Abstract · Added September 15, 2015
We previously identified a low-frequency (1.1 %) coding variant (G45R; rs200573126) in the adiponectin gene (ADIPOQ) which was the basis for a multipoint microsatellite linkage signal (LOD = 8.2) for plasma adiponectin levels in Hispanic families. We have empirically evaluated the ability of data from targeted common variants, exome chip genotyping, and genome-wide association study data to detect linkage and association to adiponectin protein levels at this locus. Simple two-point linkage and association analyses were performed in 88 Hispanic families (1,150 individuals) using 10,958 SNPs on chromosome 3. Approaches were compared for their ability to map the functional variant, G45R, which was strongly linked (two-point LOD = 20.98) and powerfully associated (p value = 8.1 × 10(-50)). Over 450 SNPs within a broad 61 Mb interval around rs200573126 showed nominal evidence of linkage (LOD > 3) but only four other SNPs in this region were associated with p values < 1.0 × 10(-4). When G45R was accounted for, the maximum LOD score across the interval dropped to 4.39 and the best p value was 1.1 × 10(-5). Linked and/or associated variants ranged in frequency (0.0018-0.50) and type (coding, non-coding) and had little detectable linkage disequilibrium with rs200573126 (r (2) < 0.20). In addition, the two-point linkage approach empirically outperformed multipoint microsatellite and multipoint SNP analysis. In the absence of data for rs200573126, family-based linkage analysis using a moderately dense SNP dataset, including both common and low-frequency variants, resulted in stronger evidence for an adiponectin locus than association data alone. Thus, linkage analysis can be a useful tool to facilitate identification of high-impact genetic variants.
0 Communities
1 Members
0 Resources
18 MeSH Terms
Genome-wide family-based linkage analysis of exome chip variants and cardiometabolic risk.
Hellwege JN, Palmer ND, Raffield LM, Ng MC, Hawkins GA, Long J, Lorenzo C, Norris JM, Ida Chen YD, Speliotes EK, Rotter JI, Langefeld CD, Wagenknecht LE, Bowden DW
(2014) Genet Epidemiol 38: 345-52
MeSH Terms: Adolescent, Adult, African Americans, Aged, Aged, 80 and over, Apolipoproteins, Atherosclerosis, Cholesterol Ester Transfer Proteins, Exome, Female, Genetic Linkage, Genetic Predisposition to Disease, Genome-Wide Association Study, Hispanic Americans, Humans, Insulin Resistance, Lipoproteins, HDL, Lod Score, Male, Middle Aged, Oligonucleotide Array Sequence Analysis, Phenotype, Polymorphism, Single Nucleotide, Young Adult
Show Abstract · Added September 15, 2015
Linkage analysis of complex traits has had limited success in identifying trait-influencing loci. Recently, coding variants have been implicated as the basis for some biomedical associations. We tested whether coding variants are the basis for linkage peaks of complex traits in 42 African-American (n = 596) and 90 Hispanic (n = 1,414) families in the Insulin Resistance Atherosclerosis Family Study (IRASFS) using Illumina HumanExome Beadchips. A total of 92,157 variants in African Americans (34%) and 81,559 (31%) in Hispanics were polymorphic and tested using two-point linkage and association analyses with 37 cardiometabolic phenotypes. In African Americans 77 LOD scores greater than 3 were observed. The highest LOD score was 4.91 with the APOE SNP rs7412 (MAF = 0.13) with plasma apolipoprotein B (ApoB). This SNP was associated with ApoB (P-value = 4 × 10(-19)) and accounted for 16.2% of the variance in African Americans. In Hispanic families, 104 LOD scores were greater than 3. The strongest evidence of linkage (LOD = 4.29) was with rs5882 (MAF = 0.46) in CETP with HDL. CETP variants were strongly associated with HDL (0.00049 < P-value <4.6 × 10(-12)), accounting for up to 4.5% of the variance. These loci have previously been shown to have effects on the biomedical traits evaluated here. Thus, evidence of strong linkage in this genome wide survey of primarily coding variants was uncommon. Loci with strong evidence of linkage was characterized by large contributions to the variance, and, in these cases, are common variants. Less compelling evidence of linkage and association was observed with additional loci that may require larger family sets to confirm.
0 Communities
1 Members
0 Resources
24 MeSH Terms
Loss-of-function mutations in Notch receptors in cutaneous and lung squamous cell carcinoma.
Wang NJ, Sanborn Z, Arnett KL, Bayston LJ, Liao W, Proby CM, Leigh IM, Collisson EA, Gordon PB, Jakkula L, Pennypacker S, Zou Y, Sharma M, North JP, Vemula SS, Mauro TM, Neuhaus IM, Leboit PE, Hur JS, Park K, Huh N, Kwok PY, Arron ST, Massion PP, Bale AE, Haussler D, Cleaver JE, Gray JW, Spellman PT, South AP, Aster JC, Blacklow SC, Cho RJ
(2011) Proc Natl Acad Sci U S A 108: 17761-6
MeSH Terms: Base Sequence, Carcinoma, Squamous Cell, Cell Communication, Codon, Nonsense, Electrophoretic Mobility Shift Assay, Humans, Lod Score, Lung Neoplasms, Molecular Sequence Data, Receptor, Notch1, Receptor, Notch2, Sequence Analysis, DNA, Signal Transduction, Skin Neoplasms
Show Abstract · Added March 10, 2014
Squamous cell carcinomas (SCCs) are one of the most frequent forms of human malignancy, but, other than TP53 mutations, few causative somatic aberrations have been identified. We identified NOTCH1 or NOTCH2 mutations in ~75% of cutaneous SCCs and in a lesser fraction of lung SCCs, defining a spectrum for the most prevalent tumor suppressor specific to these epithelial malignancies. Notch receptors normally transduce signals in response to ligands on neighboring cells, regulating metazoan lineage selection and developmental patterning. Our findings therefore illustrate a central role for disruption of microenvironmental communication in cancer progression. NOTCH aberrations include frameshift and nonsense mutations leading to receptor truncations as well as point substitutions in key functional domains that abrogate signaling in cell-based assays. Oncogenic gain-of-function mutations in NOTCH1 commonly occur in human T-cell lymphoblastic leukemia/lymphoma and B-cell chronic lymphocytic leukemia. The bifunctional role of Notch in human cancer thus emphasizes the context dependency of signaling outcomes and suggests that targeted inhibition of the Notch pathway may induce squamous epithelial malignancies.
0 Communities
1 Members
0 Resources
14 MeSH Terms
Suggestion for linkage of chromosome 1p35.2 and 3q28 to plasma adiponectin concentrations in the GOLDN Study.
Rasmussen-Torvik LJ, Pankow JS, Peacock JM, Borecki IB, Hixson JE, Tsai MY, Kabagambe EK, Arnett DK
(2009) BMC Med Genet 10: 39
MeSH Terms: Adiponectin, Adolescent, Adult, Aged, Aged, 80 and over, Body Mass Index, Chromosomes, Human, Pair 1, Chromosomes, Human, Pair 3, Enzyme-Linked Immunosorbent Assay, European Continental Ancestry Group, Female, Fenofibrate, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Hypolipidemic Agents, Lod Score, Male, Microsatellite Repeats, Middle Aged, Minnesota, Utah, Young Adult
Show Abstract · Added April 23, 2015
BACKGROUND - Adiponectin is inversely associated with obesity, insulin resistance, and atherosclerosis, but little is known about the genetic pathways that regulate the plasma level of this protein. To find novel genes that influence circulating levels of adiponectin, a genome-wide linkage scan was performed on plasma adiponectin concentrations before and after 3 weeks of treatment with fenofibrate (160 mg daily) in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) Study. We studied Caucasian individuals (n = 1121) from 190 families in Utah and Minnesota. Of these, 859 individuals from 175 families had both baseline and post-fenofibrate treatment measurements for adiponectin. Plasma adiponectin concentrations were measured with an ELISA assay. All participants were typed for microsatellite markers included in the Marshfield Mammalian Genotyping Service marker set 12, which includes 407 markers spaced at approximately 10 cM regions across the genome. Variance components analysis was used to estimate heritability and to perform genome-wide scans. Adiponectin was adjusted for age, sex, and field center. Additional models also included BMI adjustment.
RESULTS - Baseline and post-fenofibrate adiponectin measurements were highly correlated (r = 0.95). Suggestive (LOD > 2) peaks were found on chromosomes 1p35.2 and 3q28 (near the location of the adiponectin gene).
CONCLUSION - Two candidate genes, IL22RA1 and IL28RA, lie under the chromosome 1 peak; further analyses are needed to identify the specific genetic variants in this region that influence circulating adiponectin concentrations.
0 Communities
1 Members
0 Resources
23 MeSH Terms
Genetic epidemiology of subclinical cardiovascular disease in the diabetes heart study.
Bowden DW, Lehtinen AB, Ziegler JT, Rudock ME, Xu J, Wagenknecht LE, Herrington DM, Rich SS, Freedman BI, Carr JJ, Langefeld CD
(2008) Ann Hum Genet 72: 598-610
MeSH Terms: African Americans, Cardiovascular Diseases, Coronary Artery Disease, DNA, Diabetes Mellitus, Type 2, European Continental Ancestry Group, Female, Genotype, Humans, Lod Score, Male, Molecular Epidemiology, North Carolina, Pedigree, Quantitative Trait Loci, Tomography, X-Ray Computed
Show Abstract · Added February 15, 2014
A genome-wide linkage scan of 357 European American (EA) and 72 African American (AA) pedigrees multiplex for type 2 diabetes mellitus (T2DM) was performed with multipoint nonparametric QTL linkage analysis. Four subclinical measures of cardiovascular disease (CVD): coronary artery (CCP), carotid artery (CarCP), and abdominal aortic calcified plaque (AACP) and carotid artery intima-media thickness (IMT) were mapped. Analyses were adjusted for age, gender, body mass index, and (if appropriate) ethnicity and diabetes status. Evidence for linkage was observed in EA T2DM subjects to CarCP near 16p13 (LOD=4.39 at 8.4 cM; P = 0.00001). When all EA subjects were included, the LOD score was 2.52, suggesting an amplification of the linkage by diabetes. Linkage analysis of a principal components measure of vascular calcium (LOD = 3.85 at 9.3 cM on 16p in EA T2DM subjects) and bivariate analysis of CarCP X IMT (LOD = 3.77 at 9.3 cM on 16p in EA T2DM subjects) were consistent with this linkage. In addition, evidence for linkage was observed with CCP near D15S1515 (LOD = 2.34) in EAs. Additional loci on chromosomes 1, 2, 7, 10, 13, and 21 had LODs > 2.0. The identification of trait-determining polymorphisms underlying these linkages will help delineate risk factors for CVD in T2DM and the general population.
0 Communities
1 Members
0 Resources
16 MeSH Terms
Meta-analysis of 23 type 2 diabetes linkage studies from the International Type 2 Diabetes Linkage Analysis Consortium.
Guan W, Pluzhnikov A, Cox NJ, Boehnke M, International Type 2 Diabetes Linkage Analysis Consortium
(2008) Hum Hered 66: 35-49
MeSH Terms: Chromosome Mapping, Chromosomes, Human, Computer Simulation, Diabetes Mellitus, Type 2, Female, Genetic Linkage, Genetic Markers, Genetic Predisposition to Disease, Genomics, Humans, International Agencies, Lod Score, Male, Models, Genetic, Polymorphism, Single Nucleotide
Show Abstract · Added February 22, 2016
BACKGROUND - The International Type 2 Diabetes Linkage Analysis Consortium was formed to localize type 2 diabetes predisposing variants based on 23 autosomal linkage scans.
METHODS - We carried out meta-analysis using the genome scan meta-analysis (GSMA) method which divides the genome into bins of approximately 30 cM, ranks the best linkage results in each bin for each sample, and then sums the ranks across samples. We repeated the meta-analysis using 2 cM bins, and/or replacing bin ranks with measures of linkage evidence: bin maximum LOD score or bin minimum p value for bins with p value <0.05 (truncated p value). We also carried out computer simulations to assess the empirical type I error rates of these meta-analysis methods.
RESULTS - Our analyses provided modest evidence for type 2 diabetes-predisposing variants on chromosomes 4, 10, and 14 (using LOD scores or truncated p values), or chromosome 10 and 16 (using ranks). Our simulation results suggested that uneven marker density across studies results in substantial variation in empirical type I error rates for all meta-analysis methods, but that 2 cM bins and scores that make more explicit use of linkage evidence, especially the truncated p values, reduce this problem.
CONCLUSION - We identified regions modestly linked with type 2 diabetes by summarizing results from 23 autosomal genome scans.
Copyright (c) 2008 S. Karger AG, Basel.
0 Communities
1 Members
0 Resources
15 MeSH Terms
Mapping autism risk loci using genetic linkage and chromosomal rearrangements.
Autism Genome Project Consortium, Szatmari P, Paterson AD, Zwaigenbaum L, Roberts W, Brian J, Liu XQ, Vincent JB, Skaug JL, Thompson AP, Senman L, Feuk L, Qian C, Bryson SE, Jones MB, Marshall CR, Scherer SW, Vieland VJ, Bartlett C, Mangin LV, Goedken R, Segre A, Pericak-Vance MA, Cuccaro ML, Gilbert JR, Wright HH, Abramson RK, Betancur C, Bourgeron T, Gillberg C, Leboyer M, Buxbaum JD, Davis KL, Hollander E, Silverman JM, Hallmayer J, Lotspeich L, Sutcliffe JS, Haines JL, Folstein SE, Piven J, Wassink TH, Sheffield V, Geschwind DH, Bucan M, Brown WT, Cantor RM, Constantino JN, Gilliam TC, Herbert M, Lajonchere C, Ledbetter DH, Lese-Martin C, Miller J, Nelson S, Samango-Sprouse CA, Spence S, State M, Tanzi RE, Coon H, Dawson G, Devlin B, Estes A, Flodman P, Klei L, McMahon WM, Minshew N, Munson J, Korvatska E, Rodier PM, Schellenberg GD, Smith M, Spence MA, Stodgell C, Tepper PG, Wijsman EM, Yu CE, Rogé B, Mantoulan C, Wittemeyer K, Poustka A, Felder B, Klauck SM, Schuster C, Poustka F, Bölte S, Feineis-Matthews S, Herbrecht E, Schmötzer G, Tsiantis J, Papanikolaou K, Maestrini E, Bacchelli E, Blasi F, Carone S, Toma C, Van Engeland H, de Jonge M, Kemner C, Koop F, Koop F, Langemeijer M, Langemeijer M, Hijmans C, Hijimans C, Staal WG, Baird G, Bolton PF, Rutter ML, Weisblatt E, Green J, Aldred C, Wilkinson JA, Pickles A, Le Couteur A, Berney T, McConachie H, Bailey AJ, Francis K, Honeyman G, Hutchinson A, Parr JR, Wallace S, Monaco AP, Barnby G, Kobayashi K, Lamb JA, Sousa I, Sykes N, Cook EH, Guter SJ, Leventhal BL, Salt J, Lord C, Corsello C, Hus V, Weeks DE, Volkmar F, Tauber M, Fombonne E, Shih A, Meyer KJ
(2007) Nat Genet 39: 319-28
MeSH Terms: Autistic Disorder, Chromosome Aberrations, Chromosome Mapping, Family, Female, Genetic Linkage, Genetic Predisposition to Disease, Genetic Testing, Genetic Variation, Humans, Lod Score, Male, Risk Factors
Show Abstract · Added February 20, 2014
Autism spectrum disorders (ASDs) are common, heritable neurodevelopmental conditions. The genetic architecture of ASDs is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASDs by using Affymetrix 10K SNP arrays and 1,181 [corrected] families with at least two affected individuals, performing the largest linkage scan to date while also analyzing copy number variation in these families. Linkage and copy number variation analyses implicate chromosome 11p12-p13 and neurexins, respectively, among other candidate loci. Neurexins team with previously implicated neuroligins for glutamatergic synaptogenesis, highlighting glutamate-related genes as promising candidates for contributing to ASDs.
0 Communities
1 Members
0 Resources
13 MeSH Terms