We are interested in genetic mapping of complex traits and genomics and focus on 2 main topics. First, we are mapping 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. With regard to PC, we completed and published a study of a susceptibility locus we had previously mapped to human chromosome 22q. Previously, we refined this region to a 2.53 Mb interval. We now refine it to a 15 Kb interval, spanning Apolipoprotein L3 (APOL3), using family-based association analyses of 150 total PC cases from two independent family collections and 506 unrelated population controls. Analysis of the 2 independent sets of PC cases highlighted SNPs within the APOL3 locus as showing the strongest associations with HPC risk. Analysis of 15 tagSNPs across the 5 end of the locus identified six SNPs with p-values ≤2x10-4. The two independent sets of HPC cases highlight the same 15 Kb interval at the 5 end of the APOL3 gene and provide strong evidence that SNPs within this 15 Kb interval, or in strong LD with it, contribute to HPC risk. Further analyses of this locus in an independent population-based, case-control study revealed association between a SNP in the APOL3 TATAA box and PC risk. This study further characterizes the 22q locus in HPC risk and suggests that the role of this region in sporadic PC warrants additional study. In addition to the above, we have completed genotyping of now 1500 single nucleotide polymorphisms (SNPs) that include over 120 candidate genes for association with PC risk and progression in a large population-based, case control study of middle and older-aged men. Analysis of these data is ongoing, but thus far we have found interesting SNPs associated with several genes. Our general approach has been to tackle whole pathways. So, for instance, we undertook a comprehensive analysis of 48 tagSNPs in genes encoding for the VDR, the vitamin D activating enzyme 1-α-hydroxylase (CYP27B1), and deactivating enzyme 24-hydroxylase (CYP24A1). There were 139 cases with recurrence/ progression and 57 cases who died of prostate cancer with an average of 8.5 years of follow-up. Significantly altered risks of recurrence/progression were observed in relation to genotype for two VDR tagSNPs and two CYP24A1. Three VDR tagSNPs, one CYP27B1 tagSNP and five CYP24A1 tagSNPs significantly altered risks of prostate cancer death. This exploratory study shows that genetic variation within vitamin D pathway genes may alter both risk of recurrence/progression and prostate cancer-specific mortality. Our epidemiology studies of PC are also revealing. For instance, in a study of 1001 cases and 942 controls we showed a significant 21% reduction in the risk of prostate cancer among current users of aspirin compared to non-users. Long-term use of aspirin and daily use of low-dose aspirin were also associated with decreased risk and there was effect modification (p-interaction =0.02) with a genetic variant in PTGS2. With regard to breast cancer we have focused this year understanding the role of weakly penetrant alleles. For instance, genome wide association studies (GWAS) have identified FGFR2 as a breast cancer susceptibility gene in populations of European and Asian descent, but a causative variant has not yet been identified. In our study, five FGFR2 SNPs were genotyped in 1,253 African American invasive breast cancer cases and 1,245 race-matched controls. The most significant association with breast cancer risk was found with SNP rs2981578 (per allele odds ratio (OR) = 1.24, 95% confidence interval (CI) 1.04-1.47, Ptrend = 0.01). This estimate is similar to that reported in European and Asian subjects, suggesting that the same causal variant or variants are associated with risk in all populations. Associations with breast cancer risk were evaluated for seven assayable candidate causal SNPs. In the combined dataset, SNP rs2981578 was the most strongly associated, and five others could not be excluded. One or more of these variants is therefore likely to be causally associated with breast cancer risk. Two other studies have been done focusing on other genes suggested by GWAS studies of breast cancer. 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. For instance, using a multi-breed association analysis we showed that a recently acquired fgf4 retrogene causes chondrodysplasia, a short-legged phenotype that defines several common dog breeds including the corgi and basset hound. These results demonstrate the power of the canine system for mapping, provide evidence for a new type of mutation which causes disease in mammals that was previously unknown, and provides a new candidate gene for studies of humans with similar disorders. We also continue to be interested in genetics of dog breeds and have 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 shelter dogs across 60,968 SNPs. Coupling this genomic resource with external measurements from individuals as well as skeletal measurements from museum specimens we identified 51 regions of the dog genome associated with phenotypic variation among breeds in 57 traits. The complex traits include average breed body size and external body dimensions and cranial, dental and long bone shape and size. In contrast to the results from association mapping of quantitative traits in humans, we find that a small number of quantitative trait loci (≤3) explain most of the variation observed across breeds. Our results demonstrate the efficacy of mapping multiple traits in the domestic dog and highlight regions of interest for future studies of both human development and human disorders. For instance, genes associated with skull formation are likely candidates for diseases of skull dismorphology and cleft palate. 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. Also, have completed lab work for a GWAS study of gastric cancer in the Chow Chow. We have found two loci for malignant histiocytosis and fine mapped both. We are now doing mutation scanning and functional studies. Positional cloning efforts have been successful in the case of the SCC in the Poodle and following sequencing of a large region manuscript publication is underway. Bladder cancer studies reveal two loci. Fine mapping is completed, a small haplotype defines each locus. Likely genes are identified and 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 high profile papers.
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