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1.
Cancer Res ; 2021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33574088

RESUMO

Germline variation and smoking are independently associated with pancreatic ductal adenocarcinoma (PDAC). We conducted genome-wide smoking interaction analysis of PDAC using genotype data from four previous genome-wide association studies in individuals of European ancestry (7,937 cases and 11,774 controls). Examination of expression quantitative trait loci data from the Genotype-Tissue Expression Project followed by colocalization analysis was conducted to determine if there was support for common SNP(s) underlying the observed associations. Statistical tests were two sided and P-values < 5 x 10-8 were considered statistically significant. Genome-wide significant evidence of qualitative interaction was identified on chr2q21.3 in intron 5 of the transmembrane protein 163 (TMEM163) and upstream of the cyclin T2 (CCNT2). The most significant SNP using the Empirical Bayes method, in this region which included 45 significantly associated SNPs, was rs1818613 (per allele OR in never smokers 0.87, 95% CI 0.82-0.93; former smokers 1.00, 95 CI 0.91-1.07; current smokers 1.25, 95%CI 1.12-1.40, interaction P-value=3.08x10-9). Examination of the Genotype-Tissue Expression Project data demonstrated an expression quantitative trait locus in this region for TMEM163 and CCNT2 in several tissue types. Colocalization analysis supported a shared SNP, rs842357, in high LD with rs1818613 (r2=0. 94) driving both the observed interaction and the expression quantitative trait loci signals. Future studies are needed to confirm and understand the differential biologic mechanisms by smoking status that contribute to our PDAC findings.

2.
J Natl Cancer Inst ; 112(10): 1003-1012, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31917448

RESUMO

BACKGROUND: Although 20 pancreatic cancer susceptibility loci have been identified through genome-wide association studies in individuals of European ancestry, much of its heritability remains unexplained and the genes responsible largely unknown. METHODS: To discover novel pancreatic cancer risk loci and possible causal genes, we performed a pancreatic cancer transcriptome-wide association study in Europeans using three approaches: FUSION, MetaXcan, and Summary-MulTiXcan. We integrated genome-wide association studies summary statistics from 9040 pancreatic cancer cases and 12 496 controls, with gene expression prediction models built using transcriptome data from histologically normal pancreatic tissue samples (NCI Laboratory of Translational Genomics [n = 95] and Genotype-Tissue Expression v7 [n = 174] datasets) and data from 48 different tissues (Genotype-Tissue Expression v7, n = 74-421 samples). RESULTS: We identified 25 genes whose genetically predicted expression was statistically significantly associated with pancreatic cancer risk (false discovery rate < .05), including 14 candidate genes at 11 novel loci (1p36.12: CELA3B; 9q31.1: SMC2, SMC2-AS1; 10q23.31: RP11-80H5.9; 12q13.13: SMUG1; 14q32.33: BTBD6; 15q23: HEXA; 15q26.1: RCCD1; 17q12: PNMT, CDK12, PGAP3; 17q22: SUPT4H1; 18q11.22: RP11-888D10.3; and 19p13.11: PGPEP1) and 11 at six known risk loci (5p15.33: TERT, CLPTM1L, ZDHHC11B; 7p14.1: INHBA; 9q34.2: ABO; 13q12.2: PDX1; 13q22.1: KLF5; and 16q23.1: WDR59, CFDP1, BCAR1, TMEM170A). The association for 12 of these genes (CELA3B, SMC2, and PNMT at novel risk loci and TERT, CLPTM1L, INHBA, ABO, PDX1, KLF5, WDR59, CFDP1, and BCAR1 at known loci) remained statistically significant after Bonferroni correction. CONCLUSIONS: By integrating gene expression and genotype data, we identified novel pancreatic cancer risk loci and candidate functional genes that warrant further investigation.

3.
Cancer Epidemiol Biomarkers Prev ; 28(7): 1238-1245, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31015203

RESUMO

BACKGROUND: Pancreatic cancer is the fourth-leading cause of cancer death in both men and women in the United States. The currently identified common susceptibility loci account for a small fraction of estimated heritability. We sought to estimate overall heritability of pancreatic cancer and partition the heritability by variant frequencies and functional annotations. METHODS: Analysis using the genome-based restricted maximum likelihood method (GREML) was conducted on Pancreatic Cancer Case-Control Consortium (PanC4) genome-wide association study (GWAS) data from 3,568 pancreatic cancer cases and 3,363 controls of European Ancestry. RESULTS: Applying linkage disequilibrium- and minor allele frequency-stratified GREML (GREML-LDMS) method to imputed GWAS data, we estimated the overall heritability of pancreatic cancer to be 21.2% (SE = 4.8%). Across the functional groups (intronic, intergenic, coding, and regulatory variants), intronic variants account for most of the estimated heritability (12.4%). Previously identified GWAS loci explained 4.1% of the total phenotypic variation of pancreatic cancer. Mutations in hereditary pancreatic cancer susceptibility genes are present in 4% to 10% of patients with pancreatic cancer, yet our GREML-LDMS results suggested these regions explain only 0.4% of total phenotypic variance for pancreatic cancer. CONCLUSIONS: Although higher than previous studies, our estimated 21.2% overall heritability may still be downwardly biased due to the inherent limitation that the contribution of rare variants in genes with a substantive overall impact on disease are not captured when applying these commonly used methods to imputed GWAS data. IMPACT: Our work demonstrated the importance of rare and common variants in pancreatic cancer risk.


Assuntos
Neoplasias Pancreáticas/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/patologia
4.
J Mol Diagn ; 21(3): 427-436, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30872187

RESUMO

We developed a novel phasing approach, based solely on molecules and genotype frequency, that does not rely on inference of new alleles. We initiated the project because of errors that were detected in the phased 1000 Genomes Project data. The algorithm first combined identical genotypes into clusters and ranked them by descending frequency. Using alleles defined in homozygotes, it combined them to produce expected genotypes that were dismissed and subtracted them from remaining genotypes to define additional new putative alleles. Putative alleles had to be confirmed by identifying them in independent genotypes, and the process was iterated until all alleles were identified. The new approach was validated using single-molecule sequencing of eight loci, 145 (8 to 35 per locus) alleles were identified, and an average 98.2% (range, 95.0% to 99.9%) of 1000 genome individuals at these loci were explained. The accuracy of the new method was compared with that from PHASE and SHAPEIT2 to the experimentally determined genotypes based on single-molecule sequencing. Our method was comparable to PHASE and SHAPEIT2 in accuracy but was, on average, 14.6- and 10.8-fold faster, respectively.


Assuntos
Técnicas de Genotipagem/métodos , Haplótipos/genética , Alelos , Sequência de Bases , Loci Gênicos , Antígenos HLA-A/genética , Humanos , Polimorfismo de Nucleotídeo Único/genética , Reprodutibilidade dos Testes , Fatores de Tempo
5.
J Natl Cancer Inst ; 111(6): 557-567, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30541042

RESUMO

BACKGROUND: Genome-wide association studies (GWAS) identify associations of individual single-nucleotide polymorphisms (SNPs) with cancer risk but usually only explain a fraction of the inherited variability. Pathway analysis of genetic variants is a powerful tool to identify networks of susceptibility genes. METHODS: We conducted a large agnostic pathway-based meta-analysis of GWAS data using the summary-based adaptive rank truncated product method to identify gene sets and pathways associated with pancreatic ductal adenocarcinoma (PDAC) in 9040 cases and 12 496 controls. We performed expression quantitative trait loci (eQTL) analysis and functional annotation of the top SNPs in genes contributing to the top associated pathways and gene sets. All statistical tests were two-sided. RESULTS: We identified 14 pathways and gene sets associated with PDAC at a false discovery rate of less than 0.05. After Bonferroni correction (P ≤ 1.3 × 10-5), the strongest associations were detected in five pathways and gene sets, including maturity-onset diabetes of the young, regulation of beta-cell development, role of epidermal growth factor (EGF) receptor transactivation by G protein-coupled receptors in cardiac hypertrophy pathways, and the Nikolsky breast cancer chr17q11-q21 amplicon and Pujana ATM Pearson correlation coefficient (PCC) network gene sets. We identified and validated rs876493 and three correlating SNPs (PGAP3) and rs3124737 (CASP7) from the Pujana ATM PCC gene set as eQTLs in two normal derived pancreas tissue datasets. CONCLUSION: Our agnostic pathway and gene set analysis integrated with functional annotation and eQTL analysis provides insight into genes and pathways that may be biologically relevant for risk of PDAC, including those not previously identified.


Assuntos
Carcinoma Ductal Pancreático/genética , Estudo de Associação Genômica Ampla/métodos , Neoplasias Pancreáticas/genética , Estudos de Casos e Controles , Predisposição Genética para Doença , Humanos , Modelos Estatísticos , Polimorfismo de Nucleotídeo Único
6.
Nat Commun ; 9(1): 556, 2018 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-29422604

RESUMO

In 2020, 146,063 deaths due to pancreatic cancer are estimated to occur in Europe and the United States combined. To identify common susceptibility alleles, we performed the largest pancreatic cancer GWAS to date, including 9040 patients and 12,496 controls of European ancestry from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). Here, we find significant evidence of a novel association at rs78417682 (7p12/TNS3, P = 4.35 × 10-8). Replication of 10 promising signals in up to 2737 patients and 4752 controls from the PANcreatic Disease ReseArch (PANDoRA) consortium yields new genome-wide significant loci: rs13303010 at 1p36.33 (NOC2L, P = 8.36 × 10-14), rs2941471 at 8q21.11 (HNF4G, P = 6.60 × 10-10), rs4795218 at 17q12 (HNF1B, P = 1.32 × 10-8), and rs1517037 at 18q21.32 (GRP, P = 3.28 × 10-8). rs78417682 is not statistically significantly associated with pancreatic cancer in PANDoRA. Expression quantitative trait locus analysis in three independent pancreatic data sets provides molecular support of NOC2L as a pancreatic cancer susceptibility gene.


Assuntos
Carcinoma Ductal Pancreático/genética , Neoplasias Pancreáticas/genética , Bases de Dados Genéticas , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Fator 1-beta Nuclear de Hepatócito/genética , Fator 4 Nuclear de Hepatócito/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Polimorfismo de Nucleotídeo Único , Proteínas/genética , Proteínas Repressoras/genética , Tensinas/genética
7.
J Mol Diagn ; 19(3): 427-436, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28433078

RESUMO

Fields of forensics, transplantation, and paternity rely on human identity testing. Currently, this is accomplished through amplification of microsatellites followed by capillary electrophoresis. An alternative and theoretically better approach uses multiple single-nucleotide polymorphisms located within a small region of DNA, a method we initially developed using HLA-A and called haplotype counting. Herein, we validated seven additional polymorphic loci, sequenced a total of 45 individuals from three of the 1000 Genomes populations (15 from each), and determined the number of haplotypes, heterozygosity, and polymorphic information content for each locus. In addition, we developed a multiplex PCR that amplifies five of these loci simultaneously. Using this strategy with a small cohort of leukemic patients who underwent allogeneic bone marrow transplantation, we first attempted to define a threshold (0.26% recipient) by examining seven patients who tested all donor and did not relapse. Although this initial threshold will need to be confirmed in a larger cohort, we detected increased recipient DNA above this threshold 90 to 145 days earlier than microsatellite positivity, and 127 to 142 days before clinical relapse in four of eight patients (50%). Haplotype counting using these novel loci may be useful for ultrasensitive detection in fields such as bone marrow transplantation, solid organ transplant rejection, patient identification, and forensics.


Assuntos
Haplótipos/genética , Leucemia/diagnóstico , Leucemia/genética , Transplante de Medula Óssea , Quimerismo , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Masculino , Repetições de Microssatélites/genética , Reação em Cadeia da Polimerase
8.
Oncotarget ; 7(41): 66328-66343, 2016 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-27579533

RESUMO

Genome-wide association studies (GWAS) have identified common pancreatic cancer susceptibility variants at 13 chromosomal loci in individuals of European descent. To identify new susceptibility variants, we performed imputation based on 1000 Genomes (1000G) Project data and association analysis using 5,107 case and 8,845 control subjects from 27 cohort and case-control studies that participated in the PanScan I-III GWAS. This analysis, in combination with a two-staged replication in an additional 6,076 case and 7,555 control subjects from the PANcreatic Disease ReseArch (PANDoRA) and Pancreatic Cancer Case-Control (PanC4) Consortia uncovered 3 new pancreatic cancer risk signals marked by single nucleotide polymorphisms (SNPs) rs2816938 at chromosome 1q32.1 (per allele odds ratio (OR) = 1.20, P = 4.88x10 -15), rs10094872 at 8q24.21 (OR = 1.15, P = 3.22x10 -9) and rs35226131 at 5p15.33 (OR = 0.71, P = 1.70x10 -8). These SNPs represent independent risk variants at previously identified pancreatic cancer risk loci on chr1q32.1 ( NR5A2), chr8q24.21 ( MYC) and chr5p15.33 ( CLPTM1L- TERT) as per analyses conditioned on previously reported susceptibility variants. We assessed expression of candidate genes at the three risk loci in histologically normal ( n = 10) and tumor ( n = 8) derived pancreatic tissue samples and observed a marked reduction of NR5A2 expression (chr1q32.1) in the tumors (fold change -7.6, P = 5.7x10 -8). This finding was validated in a second set of paired ( n = 20) histologically normal and tumor derived pancreatic tissue samples (average fold change for three NR5A2 isoforms -31.3 to -95.7, P = 7.5x10 -4-2.0x10 -3). Our study has identified new susceptibility variants independently conferring pancreatic cancer risk that merit functional follow-up to identify target genes and explain the underlying biology.


Assuntos
Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 5/genética , Cromossomos Humanos Par 8/genética , Predisposição Genética para Doença/genética , Neoplasias Pancreáticas/genética , Conjuntos de Dados como Assunto , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único/genética
9.
J Clin Oncol ; 34(17): 2010-9, 2016 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-27114589

RESUMO

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis. Hereditary factors play a role in the development of PDAC in 3% to 5% of all patients. Surveillance of high-risk groups, may facilitate detection of PDAC at an early stage. The aim of this study was to assess whether surveillance aids detection of early-stage PDAC or precursor lesions (PRLs) and improves the prognosis. PATIENTS AND METHODS: Screening outcomes were collected from three European centers that conduct prospective screening in high-risk groups including families with clustering of PDAC (familial pancreatic cancer [FPC]) or families with a gene defect that predisposes to PDAC. The surveillance program consisted of annual magnetic resonance imaging, magnetic resonance cholangiopancreatography, and/or endoscopic ultrasound. RESULTS: Four hundred eleven asymptomatic individuals participated in the surveillance programs, including 178 CDKN2A mutation carriers, 214 individuals with FPC, and 19 BRCA1/2 or PALB2 mutation carriers. PDAC was detected in 13 (7.3%) of 178 CDKN2A mutation carriers. The resection rate was 75%, and the 5-year survival rate was 24%. Two CDKN2A mutation carriers (1%) underwent surgical resection for low-risk PRL. Two individuals (0.9%) in the FPC cohort had a pancreatic tumor, including one advanced PDAC and one early grade 2 neuroendocrine tumor. Thirteen individuals with FPC (6.1%) underwent surgical resection for a suspected PRL, but only four (1.9%) had high-risk lesions (ie, high-grade intraductal papillary mucinous neoplasms or grade 3 pancreatic intraepithelial neoplasms). One BRCA2 mutation carrier was found to have PDAC, and another BRCA2 mutation carrier and a PALB2 mutation carrier underwent surgery and were found to have low-risk PRL. No serious complications occurred as consequence of the program. CONCLUSION: Surveillance of CDNK2A mutation carriers is relatively successful, detecting most PDACs at a resectable stage. The benefit of surveillance in families with FPC is less evident.


Assuntos
Carcinoma Ductal Pancreático/diagnóstico , Neoplasias Pancreáticas/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Ductal Pancreático/diagnóstico por imagem , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Inibidor p16 de Quinase Dependente de Ciclina/genética , Detecção Precoce de Câncer , Seguimentos , Predisposição Genética para Doença , Humanos , Imagem por Ressonância Magnética , Pessoa de Meia-Idade , Mutação , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Estudos Prospectivos , Fatores de Risco
10.
Nat Genet ; 47(8): 911-6, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26098869

RESUMO

Pancreatic cancer is the fourth leading cause of cancer death in the developed world. Both inherited high-penetrance mutations in BRCA2 (ref. 2), ATM, PALB2 (ref. 4), BRCA1 (ref. 5), STK11 (ref. 6), CDKN2A and mismatch-repair genes and low-penetrance loci are associated with increased risk. To identify new risk loci, we performed a genome-wide association study on 9,925 pancreatic cancer cases and 11,569 controls, including 4,164 newly genotyped cases and 3,792 controls in 9 studies from North America, Central Europe and Australia. We identified three newly associated regions: 17q25.1 (LINC00673, rs11655237, odds ratio (OR) = 1.26, 95% confidence interval (CI) = 1.19-1.34, P = 1.42 × 10(-14)), 7p13 (SUGCT, rs17688601, OR = 0.88, 95% CI = 0.84-0.92, P = 1.41 × 10(-8)) and 3q29 (TP63, rs9854771, OR = 0.89, 95% CI = 0.85-0.93, P = 2.35 × 10(-8)). We detected significant association at 2p13.3 (ETAA1, rs1486134, OR = 1.14, 95% CI = 1.09-1.19, P = 3.36 × 10(-9)), a region with previous suggestive evidence in Han Chinese. We replicated previously reported associations at 9q34.2 (ABO), 13q22.1 (KLF5), 5p15.33 (TERT and CLPTM1), 13q12.2 (PDX1), 1q32.1 (NR5A2), 7q32.3 (LINC-PINT), 16q23.1 (BCAR1) and 22q12.1 (ZNRF3). Our study identifies new loci associated with pancreatic cancer risk.


Assuntos
Cromossomos Humanos Par 17/genética , Cromossomos Humanos Par 2/genética , Cromossomos Humanos Par 3/genética , Cromossomos Humanos Par 7/genética , Predisposição Genética para Doença/genética , Neoplasias Pancreáticas/genética , Polimorfismo de Nucleotídeo Único , Idoso , Austrália , Europa (Continente) , Feminino , Frequência do Gene , Loci Gênicos/genética , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , América do Norte , Fatores de Risco
11.
Cancer Epidemiol Biomarkers Prev ; 22(5): 803-11, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23456555

RESUMO

BACKGROUND: Increased risk of pancreatic cancer has been reported in breast cancer families carrying BRCA1and BRCA2 mutations; however, pancreatic cancer risk in mutation-negative (BRCAX) families has not been explored to date. The aim of this study was to estimate pancreatic cancer risk in high-risk breast cancer families according to the BRCA mutation status. METHODS: A retrospective cohort analysis was applied to estimate standardized incidence ratios (SIR) for pancreatic cancer. A total of 5,799 families with ≥1 breast cancer case tested for mutations in BRCA1 and/or BRCA2 were eligible. Families were divided into four classes: BRCA1, BRCA2, BRCAX with ≥2 breast cancer diagnosed before age 50 (class 3), and the remaining BRCAX families (class 4). RESULTS: BRCA1 mutation carriers were at increased risk of pancreatic cancer [SIR = 4.11; 95% confidence interval (CI), 2.94-5.76] as were BRCA2 mutation carriers (SIR = 5.79; 95% CI, 4.28-7.84). BRCAX family members were also at increased pancreatic cancer risk, which did not appear to vary by number of members with early-onset breast cancer (SIR = 1.31; 95% CI, 1.06-1.63 for class 3 and SIR = 1.30; 95% CI, 1.13-1.49 for class 4). CONCLUSIONS: Germline mutations in BRCA1 and BRCA2 are associated with an increased risk of pancreatic cancer. Members of BRCAX families are also at increased risk of pancreatic cancer, pointing to the existence of other genetic factors that increase the risk of both pancreatic cancer and breast cancer. IMPACT: This study clarifies the relationship between familial breast cancer and pancreatic cancer. Given its high mortality, pancreatic cancer should be included in risk assessment in familial breast cancer counseling.


Assuntos
Neoplasias da Mama/epidemiologia , Neoplasias Pancreáticas/epidemiologia , Idoso , Neoplasias da Mama/genética , Saúde da Família , Feminino , Genes BRCA1 , Genes BRCA2 , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/genética , Sistema de Registros , Medição de Risco
12.
BMC Med Genet ; 10: 81, 2009 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-19715579

RESUMO

BACKGROUND: A multiplicity of study designs such as gene candidate analysis, genome wide search (GWS) and, recently, whole genome association studies have been employed for the identification of the genetic components of essential hypertension (EH). Several genome-wide linkage studies of EH and blood pressure-related phenotypes demonstrate that there is no single locus with a major effect while several genomic regions likely to contain EH-susceptibility loci were validated by multiple studies. METHODS: We carried out the clinical assessment of the entire adult population in a Sardinian village (Talana) and we analyzed 16 selected families with 62 hypertensive subjects out of 267 individuals. We carried out a double GWS using a set of 902 uniformly spaced microsatellites and a high-density SNPs map on the same group of families. RESULTS: Three loci were identified by both microsatellites and SNP scans and the obtained linkage results showed a remarkable degree of similarity. These loci were identified on chromosome 2q24, 11q23.1-25 and 13q14.11-21.33. Further support to these findings is their broad description present in literature associated to EH or related phenotypes. Bioinformatic investigation of these loci shows several potential EH candidate genes, several of whom already associated to blood pressure regulation pathways. CONCLUSION: Our search for major susceptibility EH genetic factors evidences that EH in the genetic isolate of Talana is due to the contribution of several genes contained in loci identified and replicated by earlier findings in different human populations.


Assuntos
Hipertensão/genética , Escore Lod , Repetições de Microssatélites/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Linhagem
13.
PLoS One ; 4(2): e4654, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19247500

RESUMO

To better design association studies for complex traits in isolated populations it's important to understand how history and isolation moulded the genetic features of different communities. Population isolates should not "a priori" be considered homogeneous, even if the communities are not distant and part of a small region. We studied a particular area of Sardinia called Ogliastra, characterized by the presence of several distinct villages that display different history, immigration events and population size. Cultural and geographic isolation characterized the history of these communities. We determined LD parameters in 8 villages and defined population structure through high density SNPs (about 360 K) on 360 unrelated people (45 selected samples from each village). These isolates showed differences in LD values and LD map length. Five of these villages show high LD values probably due to their reduced population size and extreme isolation. High genetic differentiation among villages was detected. Moreover population structure analysis revealed a high correlation between genetic and geographic distances. Our study indicates that history, geography and biodemography have influenced the genetic features of Ogliastra communities producing differences in LD and population structure. All these data demonstrate that we can consider each village an isolate with specific characteristics. We suggest that, in order to optimize the study design of complex traits, a thorough characterization of genetic features is useful to identify the presence of sub-populations and stratification within genetic isolates.


Assuntos
Genética Populacional , Genoma Humano , Polimorfismo de Nucleotídeo Único , População Rural , Humanos , Itália , Desequilíbrio de Ligação
14.
Am J Hum Genet ; 75(6): 1015-31, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15478097

RESUMO

A powerful approach to mapping the genes for complex traits is to study isolated founder populations, in which genetic heterogeneity and environmental noise are likely to be reduced and in which extended genealogical data are often available. Using graph theory, we applied an approach that involved sampling from the large number of pairwise relationships present in an extended genealogy to reconstruct sets of subpedigrees that maximize the useful information for linkage mapping while minimizing calculation burden. We investigated, through simulation, the properties of the different sets in terms of bias in identity-by-descent (IBD) estimation and power decrease under various genetic models. We applied this approach to a small isolated population from Sardinia, the village of Talana, consisting of a unique large and complex pedigree, and performed a genomewide search through variance-components linkage analysis for serum lipid levels. We identified a region of significant linkage on chromosome 2 for total serum cholesterol and low-density lipoprotein (LDL) cholesterol. Through higher-density mapping, we obtained an increased linkage for both traits on 2q21.2-q24.1, with a LOD score of 4.3 for total serum cholesterol and of 3.9 for LDL cholesterol. A replication study was performed in an independent and larger set from a genetically differentiated isolated population of the same region of Sardinia, the village of Perdasdefogu. We obtained consistent linkage to the region for total serum cholesterol (LOD score 1.4) and LDL cholesterol (LOD score 2.2), with a level of concordance uncommon for complex traits, and refined the location of the quantitative-trait locus. Interestingly, the 2q21.1-22 region has also been linked to premature coronary heart disease in Finns, and, in the adjacent 2q14 region, significant linkage with triglycerides has been reported in Hutterites.


Assuntos
LDL-Colesterol/genética , Colesterol/genética , Mapeamento Cromossômico/métodos , Genoma Humano , Locos de Características Quantitativas/genética , Colesterol/sangue , LDL-Colesterol/sangue , Cromossomos Humanos Par 2/genética , Simulação por Computador , Genótipo , Humanos , Itália , Modelos Lineares , Escore Lod , Linhagem
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