We are interested in genetic mapping of complex traits and genomics and focus on two main topics. First, we are mapping, studying, and identifying genetic variants that increase susceptibility to breast (BC) and prostate cancer (PC) in humans. Second, we are interested in the development of the canine system for understanding the role of genetic variation in complex traits. This year most of our efforts focused on prostate cancer and canine genetic variation. Prostate Cancer We observed previously that a large number of families with putative linkage to 15q11-14 also had colon cancer segregating in the families. We did an independent genome wide analysis of colon and prostate cancer (FitzGerald et al., Eur J Hum Genet. 2010 18:1141-7), using DNA from 96 Hereditary Prostate Cancer (HPC) families, each of which has one or more first-degree relatives with colon cancer (CCa), and further analyzed the subset of families with two or more CCa cases (n=27). The strongest linkage signal was identified at 15q14 when both PC and CCa phenotypes were considered to be affected in families with two or more CCa cases (recessive HLOD=3.88). We have worked with the International Consortium of Prostate Cancer Genetics (ICPCG) to identify loci associated with prostate cancer risk by combining linkage data from over 2000 families. We genotyped 762 families with the Illumina 6000 SNP linkage panel and identified loci on chromosomes 4 and 8. The locus on 8q24 has been previously implicated in other studies as being important for both susceptibility and somatic changes. The locus on 4q13-25 is new and appears to most strongly associated with later ages at onset (Lu et al., Prostate, Jul 11 Epub ahead of print). We have also collaborated with an addition international consortium termed the PRACTICAL to do GWAS studies aimed at finding prostate cancer loci. Our role has been to validate and extend the initial findings. The initial studies from the lead group were published in 2008 in Nature Genetics. In a subsequent study we validated these results showing that loci on chromosomes 3, 6, 7, 10, 11 19 and X contained SNPs strongly associated with prostate cancer (Kote-Jarai et al., Cancer Edpidemiol Biomarkers Prev. 2008, 17: 2901). We then sought to extend previous findings by additional analysis of more individual cases and controls and denser genotyping. In a paper published in Nature Genetics in 2009, that we were part of, the Consortium reported the identification of new prostate cancer susceptibility loci on chromosomes 2, 4, 8, 11, and 22 with P values of 1.6 X 10-8 to 2.7 X 10-33 (Eeles et al., Nat Genet. 2009, 41:1116-21). Seven additional loci were very recently identified by the PRACTICAL consortium and included our contributions (Kote-Jarai et al., Nat Genet, 2011 10: 875-791). The 40 loci identified by the GWAS approach explain about 25% of the familial risk of the disease. In an independent study we collaborated with Chris Haiman to study prostate cancer in African American men (AA) (Haiman et al., Nat Genet. 2011, 43: 570-3) AA men have the strongest morbidity and mortality associated with the disease. In search of common risk alleles we contributed to a GWAS with 1,047,986 SNP markers genpotyped in 3,425 African-Americans with PC (cases) and 3,290 African-American male controls. We followed up the most significant 17 new associations and identified a new risk variant on chromosome 17q21. Further studies are needed to investigate the biological contribution of this allele to prostate cancer risk. We completed a study of 100 candidate genes and over 1000 tag SNPs analyzed on a population based case-control study of men from Western Washington state (n = 1,458 cases and 1,351 controls). We recently completed a detailed study of the inflammation pathway. Ten SNPs in seven genes (CXCL12, IL4, IL6, IL6ST, PTGS2, STAT3, and TNF) were nominally associated (P <0.05) with risk of PC in Caucasians. The most significant effect on risk was seen in the interleukin 6 signal transducer (IL6ST) gene (OR = 0.08, 95% CI: 0.01-0.63). Risk estimates for seven SNPs varied significantly according to disease aggressiveness (P(homogeneity) <0.05), These results highlight the potential importance of the inflammation pathway in PC development and progression. Canines Our canine studies canine studies focus on finding genes important in disease susceptibility and growth regulation. This work is accomplished by collaboration with dog owners, breeders and kennel clubs and not by breeding or housing any dogs on site. Several high profile papers have resulted from these efforts to date. Domestic dogs exhibit tremendous phenotypic diversity. In a recent paper we generated a high density map of canine genetic variation by genotyping 915 dogs from 80 domestic dog breeds, 83 wild canids, and 10 outbred African dogs across 60,968 single-nucleotide polymorphisms (SNPs) (Boyko et al., Plos Biol 2010). Coupling this genomic resource with external measurements from breed standards and individuals as well as skeletal measurements from museum specimens, we identify 51 regions of the dog genome associated with phenotypic variation among breeds in 57 traits. In contrast to humans we find that for across dog breeds a small number of quantitative trait loci (less or = 3) explain the majority of phenotypic variation for most of the traits we studied. In addition, many genomic regions show signatures of recent selection, with most of the highly differentiated regions being associated with breed-defining traits such as body size, coat characteristics, and ear floppiness. Our results demonstrate the efficacy of mapping multiple traits in the domestic dog using a database of genotyped individuals and highlight the important role human-directed selection has played in altering the genetic architecture of key traits in this important species. We are also continuing our series of GWAS aimed at finding loci for cancer susceptibility in the dog. Ongoing studies include mapping loci for transitional cell carcinoma (TCC) of the bladder in the Scottish terrier and West Highland White terrier and very recently the Sheltie. We continued our studies of malignant histiocytosis (MH) in the Bernese mountain dog and squamous cell carcinoma (SCC) of the digit in the poodle and the giant schnauzer with a recent paper submitted on MH. We have found two loci for malignant histiocytosis and fine mapped both. We have also begun a similar study in Flat Coated Retrievers. Positional cloning efforts have been successful in the case of the SCC in the Poodle. Bladder cancer studies also reveal two loci. Fine mapping is completed, a small haplotype defines each locus. Mutation scanning is ongoing. In summary, our work is aimed at understanding the role of genetic variation in regulating phenotypes contributing to both morphology and disease susceptibility. As a result, the past year has been defined by significant progress on all fronts and publication of multiple papers.
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