A haplotype at chromosome Xq27.2 confers susceptibility to prostate cancer.

We conducted an association study to identify risk variants for familial prostate cancer within the HPCX locus at Xq27 among Americans of Northern European descent. We investigated a total of 507 familial prostate cancer probands and 507 age-matched controls without a personal or family history of prostate cancer. The study population was subdivided into a set of training subjects to explore genetic variation of the locus potentially impacting risk of prostate cancer, and an independent set of test subjects to confirm the association and to assign significance, addressing multiple comparisons. We identified a 22.9 kb haplotype nominally associated with prostate cancer among training subjects (292 cases, 292 controls; chi(2) = 5.08, P = 0.020), that was confirmed among test subjects (215 cases, 215 controls; chi(2) = 3.73, P = 0.040). The haplotype predisposed to prostate cancer with an odds ratio of 3.41 (95% CI 1.04-11.17, P = 0.034) among test subjects. The haplotype extending from rs5907859 to rs1493189 is concordant with a prior study of the region within the Finnish founder population, and warrants further independent investigation.

Common sequence variants on 2p15 and Xp11.22 confer susceptibility to prostate cancer.

We conducted a genome-wide SNP association study on prostate cancer on over 23,000 Icelanders, followed by a replication study including over 15,500 individuals from Europe and the United States. Two newly identified variants were shown to be associated with prostate cancer: rs5945572 on Xp11.22 and rs721048 on 2p15 (odds ratios (OR) = 1.23 and 1.15; P = 3.9 x 10(-13) and 7.7 x 10(-9), respectively). The 2p15 variant shows a significantly stronger association with more aggressive, rather than less aggressive, forms of the disease.

Haplotype analysis of CYP11A1 identifies promoter variants associated with breast cancer risk.

The CYP11A1 gene encodes the cholesterol side chain cleavage enzyme that catalyzes the initial and rate-limiting step of steroidogenesis. A large number of epidemiologic studies have implicated the duration and degree of endogenous estrogen exposure in the development of breast cancer in women. Here, we conduct a systematic investigation of the role of genetic variation of the CYP11A1 gene in breast cancer risk in a study of 1193 breast cancer cases and 1310 matched controls from the Shanghai Breast Cancer Study. We characterize the genetic architecture of the CYP11A1 gene in a Chinese study population. We then genotype tagging polymorphisms to capture common variation at the locus for tests of association. Variants designating a haplotype encompassing the gene promoter are significantly associated with both increased expression (P = 1.6e-6) and increased breast cancer risk: heterozygote age-adjusted odds ratio (OR), 1.51 [95% confidence interval (95% CI), 1.19-1.91]; homozygote age-adjusted OR, 2.94 (95% CI, 1.22-7.12), test for trend, P = 5.0e-5. Among genes controlling endogenous estrogen metabolism, CYP11A1 harbors common variants that may influence expression to significantly modify risk of breast cancer.

A major zebrafish polymorphism resource for genetic mapping.

We have identified 645,088 candidate polymorphisms in zebrafish and observe a single nucleotide polymorphism (SNP) validation rate of 71% to 86%, improving with polymorphism confidence score. Variant sites are non-random, with an excess of specific novel T- and A-rich motifs. We positioned half of the polymorphisms on zebrafish genetic and physical maps as a resource for positional cloning. We further demonstrate bulked segregant analysis using the anchored SNPs as a method for high-throughput genetic mapping in zebrafish.

Genome-wide linkage identifies novel modifier loci of aganglionosis in the Sox10Dom model of Hirschsprung disease.

Hirschsprung disease (HSCR) is a complex disorder that exhibits incomplete penetrance and variable expressivity due to interactions among multiple susceptibility genes. Studies in HSCR families have identified RET-dependent modifiers for short-segment HSCR (S-HSCR), but epistatic effects in long-segment (L-HSCR) and syndromic cases have not been fully explained. SOX10 mutations contribute to syndromic HSCR cases and Sox10 alleles in mice exhibit aganglionosis and pigmentary anomalies typical of a subset of HSCR patients categorized as Waardenburg-Shah syndrome (WS4, OMIM 277580). Sox10 mutant alleles in mice exhibit strain-dependent variation in penetrance and expressivity of aganglionic megacolon analogous to the variation observed in patients with aganglionosis. In this study, we focused on enteric ganglia deficits in Sox10Dom mice and defined aganglionosis as a quantitative trait in Sox10Dom intercross progeny to investigate the contribution of strain background to variation in enteric nervous system deficits. We observe that the phenotype of Sox10Dom/+ mutants ranges over a continuum from severe aganglionosis to no detectable phenotype in the gut. To systematically identify genes that modulate Sox10-dependent aganglionosis, we performed a single nucleotide polymorphism-based genome scan in Sox10Dom/+ F1 intercross progeny. Our analysis reveals modifier loci on mouse chromosomes 3, 5, 8, 11 and 14 with distinct effects on penetrance and severity of aganglionosis. Three of these loci on chromosomes 3, 8 and 11 do not coincide with previously known aganglionosis susceptibility genes or modifier loci and offer new avenues for elucidating the genetic network that modulates this complex neurocristopathy.