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1.
Am J Hum Genet ; 104(1): 112-138, 2019 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-30595373

RESUMO

Mitochondria (MT), the major site of cellular energy production, are under dual genetic control by 37 mitochondrial DNA (mtDNA) genes and numerous nuclear genes (MT-nDNA). In the CHARGEmtDNA+ Consortium, we studied genetic associations of mtDNA and MT-nDNA associations with body mass index (BMI), waist-hip-ratio (WHR), glucose, insulin, HOMA-B, HOMA-IR, and HbA1c. This 45-cohort collaboration comprised 70,775 (insulin) to 170,202 (BMI) pan-ancestry individuals. Validation and imputation of mtDNA variants was followed by single-variant and gene-based association testing. We report two significant common variants, one in MT-ATP6 associated (p ≤ 5E-04) with WHR and one in the D-loop with glucose. Five rare variants in MT-ATP6, MT-ND5, and MT-ND6 associated with BMI, WHR, or insulin. Gene-based meta-analysis identified MT-ND3 associated with BMI (p ≤ 1E-03). We considered 2,282 MT-nDNA candidate gene associations compiled from online summary results for our traits (20 unique studies with 31 dataset consortia's genome-wide associations [GWASs]). Of these, 109 genes associated (p ≤ 1E-06) with at least 1 of our 7 traits. We assessed regulatory features of variants in the 109 genes, cis- and trans-gene expression regulation, and performed enrichment and protein-protein interactions analyses. Of the identified mtDNA and MT-nDNA genes, 79 associated with adipose measures, 49 with glucose/insulin, 13 with risk for type 2 diabetes, and 18 with cardiovascular disease, indicating for pleiotropic effects with health implications. Additionally, 21 genes related to cholesterol, suggesting additional important roles for the genes identified. Our results suggest that mtDNA and MT-nDNA genes and variants reported make important contributions to glucose and insulin metabolism, adipocyte regulation, diabetes, and cardiovascular disease.

2.
BMC Proc ; 12(Suppl 9): 37, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30263046

RESUMO

To examine whether single-nucleotide polymorphism (SNP) by methylation interactions can be detected, we analyzed GAW20 simulated triglycerides at visits 3 and 4 against baseline (visits 1 and 2) under 4 general linear models and 2 tree-based models in 200 replications of a sample of 680 individuals. Effects for SNPs, methylation cytosine-phosphate-guanine (CpG) effects, and interactions for SNP/CpG pairs were included. Causative SNPs/CpG pairs distributed on autosomal chromosomes 1 to 20 were tested to examine sensitivity. We also tested noncausative SNP/CpG pairs on chromosomes 21 and 22 to estimate the empirical null. We found reasonable power to detect the main causative loci, with the exact power depending on sample size and strength of effects at the SNP and CpG sites.

3.
BMC Geriatr ; 16: 80, 2016 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-27060904

RESUMO

BACKGROUND: The Long Life Family Study (LLFS) is an international study to identify the genetic components of various healthy aging phenotypes. We hypothesized that pedigree-specific rare variants at longevity-associated genes could have a similar functional impact on healthy phenotypes. METHODS: We performed custom hybridization capture sequencing to identify the functional variants in 464 candidate genes for longevity or the major diseases of aging in 615 pedigrees (4,953 individuals) from the LLFS, using a multiplexed, custom hybridization capture. Variants were analyzed individually or as a group across an entire gene for association to aging phenotypes using family based tests. RESULTS: We found significant associations to three genes and nine single variants. Most notably, we found a novel variant significantly associated with exceptional survival in the 3' UTR OBFC1 in 13 individuals from six pedigrees. OBFC1 (chromosome 10) is involved in telomere maintenance, and falls within a linkage peak recently reported from an analysis of telomere length in LLFS families. Two different algorithms for single gene associations identified three genes with an enrichment of variation that was significantly associated with three phenotypes (GSK3B with the Healthy Aging Index, NOTCH1 with diastolic blood pressure and TP53 with serum HDL). CONCLUSIONS: Sequencing analysis of family-based associations for age-related phenotypes can identify rare or novel variants.


Assuntos
Estudos de Associação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Longevidade/genética , Linhagem , Fenótipo , Idoso , Feminino , Testes Genéticos , Variação Genética/genética , Humanos , Masculino
4.
Prostate ; 76(5): 479-90, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26708993

RESUMO

BACKGROUND: Because a significant number of patients with prostate cancer (PCa) are diagnosed with disease unlikely to cause harm, genetic markers associated with clinically aggressive PCa have potential clinical utility. Since cell cycle checkpoint dysregulation is crucial for the development and progression of cancer, we tested the hypothesis that common germ-line variants within cell cycle genes were associated with aggressive PCa. METHODS: Via a two-stage design, 364 common sequence variants in 88 genes were tested. The initial stage consisted of 258 aggressive PCa patients and 442 controls, and the second stage added 384 aggressive PCa Patients and 463 controls. European-American and African-American samples were analyzed separately. In the first stage, SNPs were typed by Illumina Goldengate assay while in the second stage SNPs were typed by Pyrosequencing assays. Genotype frequencies between cases and controls were compared using logistical regression analysis with additive, dominant and recessive models. RESULTS: Eleven variants within 10 genes (CCNC, CCND3, CCNG1, CCNT2, CDK6, MDM2, SKP2, WEE1, YWHAB, YWHAH) in the European-American population and nine variants in 7 genes (CCNG1, CDK2, CDK5, MDM2, RB1, SMAD3, TERF2) in the African-American population were found to be associated with aggressive PCa using at least one model. Of particular interest, CCNC (rs3380812) was associated with risk in European-American cohorts from both institutions. CDK2 (rs1045435) and CDK5 (rs2069459) were associated with risk in the African-American cohorts from both institutions. Lastly, variants within MDM2 and CCNG1 were protective for aggressive PCa in both ethnic groups. CONCLUSIONS: This study confirms that polymorphisms within cell cycle genes are associated with clinically aggressive PCa. Validation of these markers in additional populations is necessary, but these markers may help identify patients at risk for potentially lethal carcinoma.


Assuntos
Proteínas de Ciclo Celular/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Próstata/patologia , Neoplasias da Próstata/genética , Adulto , Afro-Americanos/genética , Idoso , Idoso de 80 Anos ou mais , Pontos de Checagem do Ciclo Celular/genética , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/patologia
5.
J Gerontol A Biol Sci Med Sci ; 70(8): 1003-8, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25758594

RESUMO

BACKGROUND: The Healthy Aging Index (HAI) is a tool for measuring the extent of health and disease across multiple systems. METHODS: We conducted a genome-wide association study and a genome-wide linkage analysis to map quantitative trait loci associated with the HAI and a modified HAI weighted for mortality risk in 3,140 individuals selected for familial longevity from the Long Life Family Study. The genome-wide association study used the Long Life Family Study as the discovery cohort and individuals from the Cardiovascular Health Study and the Framingham Heart Study as replication cohorts. RESULTS: There were no genome-wide significant findings from the genome-wide association study; however, several single-nucleotide polymorphisms near ZNF704 on chromosome 8q21.13 were suggestively associated with the HAI in the Long Life Family Study (p < 10(-) (6)) and nominally replicated in the Cardiovascular Health Study and Framingham Heart Study. Linkage results revealed significant evidence (log-odds score = 3.36) for a quantitative trait locus for mortality-optimized HAI in women on chromosome 9p24-p23. However, results of fine-mapping studies did not implicate any specific candidate genes within this region of interest. CONCLUSIONS: ZNF704 may be a potential candidate gene for studies of the genetic underpinnings of longevity.


Assuntos
Envelhecimento , Ligação Genética , Estudo de Associação Genômica Ampla , Apolipoproteínas E/genética , Proteína Forkhead Box O3 , Fatores de Transcrição Forkhead/genética , Humanos , Longevidade , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas
6.
Hum Genet ; 133(7): 919-30, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24604477

RESUMO

Non-high-density lipoprotein cholesterol(NHDL) is an independent and superior predictor of CVD risk as compared to low-density lipoprotein alone. It represents a spectrum of atherogenic lipid fractions with possibly a distinct genomic signature. We performed genome-wide association studies (GWAS) to identify loci influencing baseline NHDL and its postprandial lipemic (PPL) response. We carried out GWAS in 4,241 participants of European descent. Our discovery cohort included 928 subjects from the Genetics of Lipid-Lowering Drugs and Diet Network Study. Our replication cohorts included 3,313 subjects from the Heredity and Phenotype Intervention Heart Study and Family Heart Study. A linear mixed model using the kinship matrix was used for association tests. The best association signal was found in a tri-genic region at RHOQ-PIGF-CRIPT for baseline NHDL (lead SNP rs6544903, discovery p = 7e-7, MAF = 2 %; validation p = 6e-4 at 0.1 kb upstream neighboring SNP rs3768725, and 5e-4 at 0.7 kb downstream neighboring SNP rs6733143, MAF = 10 %). The lead and neighboring SNPs were not perfect surrogate proxies to each other (D' = 1, r (2) = 0.003) but they seemed to be partially dependent (likelihood ration test p = 0.04). Other suggestive loci (discovery p < 1e-6) included LOC100419812 and LOC100288337 for baseline NHDL, and LOC100420502 and CDH13 for NHDL PPL response that were not replicated (p > 0.01). The current and first GWAS of NHDL yielded an interesting common variant in RHOQ-PIGF-CRIPT influencing baseline NHDL levels. Another common variant in CDH13 for NHDL response to dietary high-fat intake challenge was also suggested. Further validations for both loci from large independent studies, especially interventional studies, are warranted.


Assuntos
Colesterol/sangue , Estudo de Associação Genômica Ampla , Proteínas Adaptadoras de Transdução de Sinal/genética , Adulto , Idoso , Caderinas/genética , HDL-Colesterol , Estudos de Coortes , Feminino , Variação Genética , Genótipo , Humanos , Modelos Lineares , Metabolismo dos Lipídeos , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Período Pós-Prandial , Proteínas rho de Ligação ao GTP/genética
7.
Metabolism ; 63(4): 461-8, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24405752

RESUMO

OBJECTIVE: Glycated hemoglobin (HbA1c) is a stable index of chronic glycemic status and hyperglycemia associated with progressive development of insulin resistance and frank diabetes. It is also associated with premature aging and increased mortality. To uncover novel loci for HbA1c that are associated with healthy aging, we conducted a genome-wide association study (GWAS) using non-diabetic participants in the Long Life Family Study (LLFS), a study with familial clustering of exceptional longevity in the US and Denmark. METHODS: A total of 4088 non-diabetic subjects from the LLFS were used for GWAS discoveries, and a total of 8231 non-diabetic subjects from the Atherosclerosis Risk in Communities Study (ARIC, in the MAGIC Consortium) and the Health, Aging, and Body Composition Study (HABC) were used for GWAS replications. HbA1c was adjusted for age, sex, centers, 20 principal components, without and with BMI. A linear mixed effects model was used for association testing. RESULTS: Two known loci at GCK rs730497 (or rs2908282) and HK1 rs17476364 were confirmed (p<5e-8). Of 25 suggestive (5e-8

Assuntos
Estudo de Associação Genômica Ampla , Hemoglobina A Glicada/metabolismo , Longevidade , Idoso , Estudos de Coortes , Dinamarca , Diabetes Mellitus/sangue , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Estados Unidos
8.
Aging (Albany NY) ; 5(9): 653-61, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24244950

RESUMO

Despite evidence from family studies that there is a strong genetic influence upon exceptional longevity, relatively few genetic variants have been associated with this trait. One reason could be that many genes individually have such weak effects that they cannot meet standard thresholds of genome wide significance, but as a group in specific combinations of genetic variations, they can have a strong influence. Previously we reported that such genetic signatures of 281 genetic markers associated with about 130 genes can do a relatively good job of differentiating centenarians from non­centenarians particularly if the centenarians are 106 years and older. This would support our hypothesis that the genetic influence upon exceptional longevity increases with older and older (and rarer) ages. We investigated this list of markers using similar genetic data from 5 studies of centenarians from the USA, Europe and Japan. The results from the meta­analysis show that many of these variants are associated with survival to these extreme ages in other studies. Since many centenarians compress morbidity and disability towards the end of their lives, these results could point to biological pathways and therefore new therapeutics to increase years of healthy lives in the general population.


Assuntos
Variação Genética , Longevidade/genética , Idoso de 80 Anos ou mais , Envelhecimento/genética , Doença de Alzheimer/genética , Estudos de Casos e Controles , Doença da Artéria Coronariana/genética , Feminino , Redes Reguladoras de Genes , Marcadores Genéticos , Estudo de Associação Genômica Ampla , Humanos , Masculino , Polimorfismo de Nucleotídeo Único
9.
Front Genet ; 4: 65, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23658558

RESUMO

Personality traits have been shown to be associated with longevity and healthy aging. In order to discover novel genetic modifiers associated with personality traits as related with longevity, we performed a genome-wide association study (GWAS) on personality factors assessed by NEO-five-factor inventory in individuals enrolled in the Long Life Family Study (LLFS), a study of 583 families (N up to 4595) with clustering for longevity in the United States and Denmark. Three SNPs, in almost perfect LD, associated with agreeableness reached genome-wide significance (p < 10(-8)) and replicated in an additional sample of 1279 LLFS subjects, although one (rs9650241) failed to replicate and the other two were not available in two independent replication cohorts, the Baltimore Longitudinal Study of Aging and the New England Centenarian Study. Based on 10,000,000 permutations, the empirical p-value of 2 × 10(-7) was observed for the genome-wide significant SNPs. Seventeen SNPs that reached marginal statistical significance in the two previous GWASs (p-value <10(-4) and 10(-5)), were also marginally significantly associated in this study (p-value <0.05), although none of the associations passed the Bonferroni correction. In addition, we tested age-by-SNP interactions and found some significant associations. Since scores of personality traits in LLFS subjects change in the oldest ages, and genetic factors outweigh environmental factors to achieve extreme ages, these age-by-SNP interactions could be a proxy for complex gene-gene interactions affecting personality traits and longevity.

10.
Genet Epidemiol ; 35 Suppl 1: S22-8, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22128054

RESUMO

Next-generation sequencing of large numbers of individuals presents challenges in data preparation, quality control, and statistical analysis because of the rarity of the variants. The Genetic Analysis Workshop 17 (GAW17) data provide an opportunity to survey existing methods and compare these methods with novel ones. Specifically, the GAW17 Group 2 contributors investigate existing and newly proposed methods and study design strategies to identify rare variants, predict functional variants, and/or examine quality control. We introduce the eight Group 2 papers, summarize their approaches, and discuss their strengths and weaknesses. For these investigations, some groups used only the genotype data, whereas others also used the simulated phenotype data. Although the eight Group 2 contributions covered a wide variety of topics under the general idea of identifying rare variants, they can be grouped into three broad categories according to their common research interests: functionality of variants and quality control issues, family-based analyses, and association analyses of unrelated individuals. The aims of the first subgroup were quite different. These were population structure analyses that used rare variants to predict functionality and examine the accuracy of genotype calls. The aims of the family-based analyses were to select which families should be sequenced and to identify high-risk pedigrees; the aim of the association analyses was to identify variants or genes with regression-based methods. However, power to detect associations was low in all three association studies. Thus this work shows opportunities for incorporating rare variants into the genetic and statistical analyses of common diseases.


Assuntos
Variação Genética , Epidemiologia Molecular/métodos , Epidemiologia Molecular/normas , Algoritmos , Exoma/genética , Predisposição Genética para Doença , Projeto Genoma Humano , Humanos , Controle de Qualidade , Análise de Regressão , Análise de Sequência/normas
11.
Hum Hered ; 70(1): 55-62, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20551674

RESUMO

Variance components (VC) and the Bayesian Markov chain Monte Carlo (MCMC) analysis are two of the widely used linkage analysis approaches to mapping genes for complex quantitative traits. Both approaches can handle extended pedigrees and multiple markers and do not require a prespecified genetic model. In this study, we used simulated data to compare the performance of these two approaches with the traditional parametric linkage analysis. Using simulated data sets without linkage between a quantitative trait and the markers, we estimated a critical value for various test scores used in VC or MCMC and the location (LOC) score at a fixed level of significance (5%). These critical values were then used to determine the power for the three methods for simulated data sets with linkage. We found that both the VC and MCMC approaches worked well, compared with the LOC score, when there was only one gene underlying the quantitative trait; however, VC had higher power than the other methods in a simulation study of a complex phenotype influenced by more than one gene. We also compared two implementations of MCMC analysis, finding interpretation of results using the log of placement score was more accurate for linkage inference than the Bayes factor but required much more intensive simulation studies.


Assuntos
Ligação Genética , Teorema de Bayes , Humanos , Cadeias de Markov , Método de Monte Carlo
13.
BMC Proc ; 3 Suppl 7: S4, 2009 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-20018031

RESUMO

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

14.
BMC Proc ; 3 Suppl 7: S98, 2009 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-20018095

RESUMO

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

15.
Genet Epidemiol ; 33 Suppl 1: S81-7, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19924706

RESUMO

Group 12 evaluated approaches to incorporate outside information or otherwise optimize traditional linkage and association analyses. The abundance of available data allowed exploration of identity-by-descent (IBD) estimation, score statistics, formal combination of linkage and association testing, significance estimation, and replication. We observed that IBD estimation can be optimized with a subset of marker data while estimation of inheritance vectors can provide both IBD estimates and a measure of their uncertainty. Score statistics incorporating covariates or combining association and linkage information performed at least as well as standard approaches while requiring less computation time. The formal combination of linkage and association methods may be fruitful, although the nature of the simulated data limited our conclusions. Estimation of significance may be improved through simulation, correction for cryptic relatedness, and the inclusion of prior information. Replication using real data provided consistent results, though the same was not true of simulated data replicates. Overall, we found that increasing the amount of available data limits analyses due to computational constraints and motivates the need to improve methods for the identification of complex-trait genes.


Assuntos
Ligação Genética , Estudo de Associação Genômica Ampla/métodos , Feminino , Marcadores Genéticos , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Humanos , Masculino , Epidemiologia Molecular , Linhagem , Fenótipo
16.
Hum Hered ; 68(3): 209-19, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19521103

RESUMO

OBJECTIVE: While multiple lines of evidence suggest the importance of genetic contributors to risk of preterm birth, the nature of the genetic component has not been identified. We perform segregation analyses to identify the best fitting genetic model for gestational age, a quantitative proxy for preterm birth. METHODS: Because either mother or infant can be considered the proband from a preterm delivery and there is evidence to suggest that genetic factors in either one or both may influence the trait, we performed segregation analysis for gestational age either attributed to the infant (infant's gestational age), or the mother (by averaging the gestational ages at which her children were delivered), using 96 multiplex preterm families. RESULTS: These data lend further support to a genetic component contributing to birth timing since sporadic (i.e. no familial resemblance) and nontransmission (i.e. environmental factors alone contribute to gestational age) models are strongly rejected. Analyses of gestational age attributed to the infant support a model in which mother's genome and/or maternally-inherited genes acting in the fetus are largely responsible for birth timing, with a smaller contribution from the paternally-inherited alleles in the fetal genome. CONCLUSION: Our findings suggest that genetic influences on birth timing are important and likely complex.


Assuntos
Genoma/genética , Idade Gestacional , Mães , Nascimento Prematuro/genética , Grupo com Ancestrais do Continente Africano/genética , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Linhagem , Gravidez
17.
Genet Epidemiol ; 31 Suppl 1: S96-102, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-18046760

RESUMO

The research presented in group 11 of the Genetic Analysis Workshop 15 (GAW15) falls into two major themes: Model selection approaches for gene mapping (both Bayesian and Frequentist); and other Bayesian methods. These methods either allow relaxation of some of the common assumptions, such as mode of inheritance, for studying complicated genetic systems, or allow incorporation of additional information into the model. Over half of the groups applied model selection methods on all three data sets, using models in which genetic markers were used as predictors for linkage, phenotype expression, or transmission to an affected offspring. Most groups employed variations of Stochastic Search Variable Selection as the model selection method of choice. A brief review of this class of methods is given in this summary paper, followed by highlights of other methods and overall summaries of each contribution to the GAW15 presentation group 11. These group contributions exhibit the value of framing genetic problems in terms of model selection, and highlight the impact of variable selection for gene mapping.


Assuntos
Teorema de Bayes , Modelos Genéticos , Ligação Genética , Humanos , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Processos Estocásticos
18.
Hum Mol Genet ; 16(20): 2463-71, 2007 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-17652099

RESUMO

Hypertrophic cardiomyopathy (HCM) is a disease of mutant sarcomeric proteins (except for phenocopy). Cardiac hypertrophy is the clinical diagnostic hallmark of HCM and a major determinant of morbidity and mortality in various cardiovascular diseases. However, there is remarkable variability in expression of hypertrophy, even among HCM patients with identical causal mutations. We hypothesized modifier genes are partly responsible for the variation in hypertrophic expressivity. To map the modifier loci, we typed 811 short-tandem repeat markers ( approximately 5 cMdense) in 100 members of an HCM family including 36 with the InsG791 mutation in MYBPC3. We performed oligogenic simultaneous segregation and linkage analyses using Markov Chain Monte Carlo methods and detected linkage on 3q26.2 (180 cM), 10p13 (41 cM), 17q24 (108 cM) with log of the posterior placement probability ratio (LOP) of 3.51, 4.86 and 4.17, respectively, and suggestive linkage (LOP of 2.40) on 16q12.2 (73 cM). The effect sizes varied according to the modifier locus, age and sex. It ranged from approximately 8 g shift in left ventricular mass for 10p13 locus heterozygosity for the common allele to approximately 90 g shift for 3q26.2 locus homozygosity for the uncommon allele. Refining the 10p13 locus restricted the candidate modifier genes to ITGA8, C10orf97 (CARP) and PTER. ITGA8 and CARP are biologically plausible candidates as they are implicated in cardiac fibrosis and apoptosis, respectively. Since cardiac hypertrophy is a major determinant of total and cardiovascular mortality and morbidity, regardless of the etiology, identification of the specific modifier genes could have significant prognostic and therapeutic implications for various cardiovascular diseases.


Assuntos
Cardiomiopatia Hipertrófica/genética , Mapeamento Cromossômico , Locos de Características Quantitativas , Adolescente , Adulto , Proteínas de Transporte/genética , Cromossomos Humanos , Família , Feminino , Ligação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Fenótipo
20.
BMC Proc ; 1 Suppl 1: S108, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-18466448

RESUMO

The CEPH samples are an invaluable resource for mapping genes that contribute to traits that can be measured in cell lines. With the many markers that have already been genotyped for the Centre d'Etude du Polymorphisme Humain (CEPH) pedigrees and are readily available, one need only obtain phenotypes to conduct a linkage analysis. For Genetic Analysis Workshop 15 (GAW15), over 3000 expression levels of genes in lymphoblastoid cells in 14 of the CEPH pedigrees were provided. For this study, eight of these expression levels were selected to obtain a spectrum of heritabilities, three were selected based on linkage results with traditional LOD scores >3, and one trait was selected at random. A Bayesian Monte Carlo Markov chain oligogenic segregation and linkage analysis was conducted on each of these 12 traits using the genome-wide single-nucleotide polymorphism linkage markers provided for GAW15. Our goal was to assess the ability of these methods to map genes in the CEPH pedigrees. Surprisingly, positive linkage signals were found for all 12 traits, even those with a very small traditionally calculated heritability. However, the portion of the variance attributed to genetic sources by the oligogenic segregation analysis differed substantially in some cases from the traditional heritability. It appears that genetic variance estimated from oligogenic segregation analysis may be a better indicator of whether genes can be mapped for complex traits than traditional heritability.

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