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ABSTRACT: Homologous long segments along the genomes of close or remote relatives that are identical by descent (IBD) from a common ancestor provide clues for recent events in human genetics. We set out to extensively map such IBD segments in large cohorts and investigate their distribution within and across different populations. We report analysis of several data sets, demonstrating that IBD is more common than expected by naïve models of population genetics. We show that the frequency of IBD pairs is population dependent and can be used to cluster individuals into populations, detect a homogeneous subpopulation within a larger cohort, and infer bottleneck events in such a subpopulation. Specifically, we show that Ashkenazi Jewish individuals are all connected through transitive remote family ties evident by sharing of 50 cM IBD to a publicly available data set of less than 400 individuals. We further expose regions where long-range haplotypes are shared significantly more often than elsewhere in the genome, observed across multiple populations, and enriched for common long structural variation. These are inconsistent with recent relatedness and suggest ancient common ancestry, with limited recombination between haplotypes.
Molecular Biology and Evolution 02/2012; 29(2):473-86. · 5.55 Impact Factor
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Mengling Liu,
Linda Rogers,
Qinyi Cheng,
Yongzhao Shao,
Maria Elena Fernandez-Beros,
Joel N Hirschhorn,
Helen N Lyon,
Zofia K Z Gajdos,
Sailaja Vedantam, Peter Gregersen, [......],
Bertram Bleck,
Adaikalavan Ramasamy,
Anna-Liisa Hartikainen,
Marjo-Riitta Jarvelin,
Mikko Kuokkanen,
Tarja Laitinen,
Johan Eriksson,
Terho Lehtimäki,
Olli T Raitakari,
Joan Reibman
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ABSTRACT: Thymic stromal lymphopoietin (TSLP), an IL7-like cytokine produced by bronchial epithelial cells is upregulated in asthma and induces dendritic cell maturation supporting a Th2 response. Environmental pollutants, including tobacco smoke and diesel exhaust particles upregulate TSLP suggesting that TSLP may be an interface between environmental pollution and immune responses in asthma. Since asthma is prevalent in urban communities, variants in the TSLP gene may be important in asthma susceptibility in these populations.
To determine whether genetic variants in TSLP are associated with asthma in an urban admixed population. METHODOLOGY AND MAIN RESULTS: Ten tag-SNPs in the TSLP gene were analyzed for association with asthma using 387 clinically diagnosed asthmatic cases and 212 healthy controls from an urban admixed population. One SNP (rs1898671) showed nominally significant association with asthma (odds ratio (OR) = 1.50; 95% confidence interval (95% CI): 1.09-2.05, p = 0.01) after adjusting for age, BMI, income, education and population stratification. Association results were consistent using two different approaches to adjust for population stratification. When stratified by smoking status, the same SNP showed a significantly increased risk associated with asthma in ex-smokers (OR = 2.00, 95% CI: 1.04-3.83, p = 0.04) but not significant in never-smokers (OR = 1.34; 95% CI: 0.93-1.94, p = 0.11). Haplotype-specific score test indicated that an elevated risk for asthma was associated with a specific haplotype of TSLP involving SNP rs1898671 (OR = 1.58, 95% CI: 1.10-2.27, p = 0.01). Association of this SNP with asthma was confirmed in an independent large population-based cohort consortium study (OR = 1.15, 95% CI: 1.07-1.23, p = 0.0003) and the results stratified by smoking status were also validated (ex-smokers: OR = 1.21, 95% CI: 1.08-1.34, p = 0.003; never-smokers: OR = 1.06, 95% CI: 0.94-1.17, p = 0.33).
Genetic variants in TSLP may contribute to asthma susceptibility in admixed urban populations with a gene and environment interaction.
PLoS ONE 01/2011; 6(9):e25099. · 4.09 Impact Factor
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Tomas Kirchhoff,
Zhang-qun Chen,
Bert Gold,
Prodipto Pal,
Mia M Gaudet,
Kristi Kosarin,
Douglas A Levine, Peter Gregersen,
Sara Spencer,
Megan Harlan,
Mark Robson,
Robert J Klein,
Clifford A Hudis,
Larry Norton,
Michael Dean,
Kenneth Offit
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ABSTRACT: Recently, we identified a novel breast cancer susceptibility locus at 6q22.33 following a genome-wide association study in the Ashkenazi Jewish genetic isolate. To replicate these findings, we did a case-control association analysis on 6q22.33 (rs2180341) in an additional 487 Ashkenazi Jewish breast cancer cases and in an independent non-Jewish, predominantly European American, population of 1,466 breast cancer cases and 1,467 controls. We confirmed the 6q22.33 association with breast cancer risk in the replication cohorts [per-allele odds ratio (OR), 1.18; 95% confidence interval (95% CI), 1.04-1.33; P = 0.0083], with the strongest effect in the aggregate meta-analysis of 3,039 breast cancer cases and 2,616 Ashkenazi Jewish and non-Jewish controls (per-allele OR, 1.24; 95% CI, 1.13-1.36; P = 3.85 x 10(-7)). We also showed that the association was slightly stronger with estrogen receptor-positive tumors (per-allele OR, 1.35; 95% CI, 1.20-1.51; P = 2.2 x 10(-5)) compared with estrogen receptor-negative tumors (per-allele OR, 1.19; 95% CI, 0.97-1.47; P = 0.1). Furthermore, this study provides a novel insight into the functional significance of 6q22.33 in breast cancer susceptibility. Due to the stronger association of 6q22.33 with estrogen receptor-positive breast cancer, we examined the effect of candidate genes on estrogen receptor response elements. Upon transfection of overexpressed RNF146 in the MCF-7 breast cancer cell line, we observed diminished expression of an estrogen receptor response element reporter construct. This study confirms the association of 6q22.33 with breast cancer, with slightly stronger effect in estrogen receptor-positive tumors. Further functional studies of candidate genes are in progress, and a large replication analysis is being completed as part of an international consortium.
Cancer Epidemiology Biomarkers & Prevention 09/2009; 18(9):2468-75. · 4.12 Impact Factor
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Bert Gold,
Tomas Kirchhoff,
Stefan Stefanov,
James Lautenberger,
Agnes Viale,
Judy Garber,
Eitan Friedman,
Steven Narod,
Adam B Olshen, Peter Gregersen,
Kristi Kosarin,
Adam Olsh,
Julie Bergeron,
Nathan A Ellis,
Robert J Klein,
Andrew G Clark,
Larry Norton,
Michael Dean,
Jeff Boyd,
Kenneth Offit
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ABSTRACT: We performed a three-phase genome-wide association study (GWAS) using cases and controls from a genetically isolated population, Ashkenazi Jews (AJ), to identify loci associated with breast cancer risk. In the first phase, we compared allele frequencies of 150,080 SNPs in 249 high-risk, BRCA1/2 mutation-negative AJ familial cases and 299 cancer-free AJ controls using chi(2) and the Cochran-Armitage trend tests. In the second phase, we genotyped 343 SNPs from 123 regions most significantly associated from stage 1, including 4 SNPs from the FGFR2 region, in 950 consecutive AJ breast cancer cases and 979 age-matched AJ controls. We replicated major associations in a third independent set of 243 AJ cases and 187 controls. We obtained a significant allele P value of association with AJ breast cancer in the FGFR2 region (P = 1.5 x 10(-5), odds ratio (OR) 1.26, 95% confidence interval (CI) 1.13-1.40 at rs1078806 for all phases combined). In addition, we found a risk locus in a region of chromosome 6q22.33 (P = 2.9 x 10(-8), OR 1.41, 95% CI 1.25-1.59 at rs2180341). Using several SNPs at each implicated locus, we were able to verify associations and impute haplotypes. The major haplotype at the 6q22.33 locus conferred protection from disease, whereas the minor haplotype conferred risk. Candidate genes in the 6q22.33 region include ECHDC1, which encodes a protein involved in mitochondrial fatty acid oxidation, and also RNF146, which encodes a ubiquitin protein ligase, both known pathways in breast cancer pathogenesis.
Proceedings of the National Academy of Sciences 04/2008; 105(11):4340-5. · 9.68 Impact Factor
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Kenneth Offit,
Heather Pierce,
Tomas Kirchhoff,
Prema Kolachana,
Beth Rapaport, Peter Gregersen,
Steven Johnson,
Orit Yossepowitch,
Helen Huang,
Jaya Satagopan,
Mark Robson,
Lauren Scheuer,
Khedoudja Nafa,
Nathan Ellis
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ABSTRACT: The 1100delC CHEK2 allele has been associated with a 1.4-4.7 fold increased risk for breast cancer in women carrying this mutation. While the frequency of 1100delC was 1.1-1.4% in healthy Finnish controls, the frequency of this allele in a North American control population and in North American breast cancer kindreds remains unclear.
We genotyped 1665 healthy New York volunteers and 300 cases of breast cancer for the CHEK2*1100delC.
The overall frequency of the 1100delC was 3/300 (1.0%) among all cases with either a family history of breast cancer (n = 192) or a personal history of breast cancer (n = 108, of which 46 were bilateral, 46 unilateral, and 16 were male breast cancer cases), compared to a frequency of 5/1665 (0.3%) in healthy controls (p = 0.1). There was no difference in allele frequency among Ashkenazi and non-Ashkenazi controls.
The relatively low breast cancer penetrance of this allele, along with the low population frequency, will limit the clinical applicability of germline testing for CHEK2*1100delC in North American kindreds.
BMC Medical Genetics 02/2003; 4:1. · 2.33 Impact Factor
