Jathine Wong

PedGenie: an analysis approach for genetic association testing in extended pedigrees and genealogies of arbitrary size

BackgroundWe present a general approach to perform association analyses in pedigrees of arbitrary size and structure, which also allows for a mixture of pedigree members and independent individuals to be analyzed together, to test genetic markers and qualitative or quantitative traits. Our software, PedGenie, uses Monte Carlo significance testing to provide a valid test for related individuals that can be applied to any test statistic, including transmission disequilibrium statistics. Single locus at a time, composite genotype tests, and haplotype analyses may all be performed. We illustrate the validity and functionality of PedGenie using simulated and real data sets. For the real data set, we evaluated the role of two tagging-single nucleotide polymorphisms (tSNPs) in the DNA repair gene, NBS1, and their association with female breast cancer in 462 cases and 572 controls selected to be BRCA1/2 mutation negative from 139 high-risk Utah breast cancer families.ResultsThe results from PedGenie were shown to be valid both for accurate p-value calculations and consideration of pedigree structure in the simulated data set. A nominally significant association with breast cancer was observed with the NBS1 tSNP rs709816 for carriage of the rare allele (OR = 1.61, 95% CI = 1.10–2.35, p = 0.019).ConclusionPedGenie is a flexible and valid statistical tool that is intuitively simple to understand, makes efficient use of all the data available from pedigrees without requiring trimming, and is flexible to the types of tests to which it can be applied. Further, our analyses of real data indicate NBS1 may play a role in the genetic etiology of heritable breast cancer.

Increased Risk of Colorectal Neoplasia Among Family Members of Patients With Colorectal Cancer: A Population-Based Study in Utah

BACKGROUND & AIMS Colorectal cancer (CRC) frequently develops in multiple members of the same families, but more data are needed to prepare effective screening guidelines. We quantified the risk of CRC and adenomas in first-degree relatives (FDRs) and second-degree relatives and first cousins of individuals with CRC, and stratified risk based on age at cancer diagnosis. METHODS We performed a case-control study of Utah residents, 50-80 years old, who underwent colonoscopy from 1995 through 2009. Index cases (exposed to colonoscopy) were colonoscopy patients with a CRC diagnosis. Age- and sex-matched individuals, unexposed to colonoscopy (controls) were selected to form the comparison groups for determining risk in relatives. Colonoscopy results were linked to cancer and pedigree information from the Utah Population Database to investigate familial aggregation of colorectal neoplasia using Cox regression analysis. RESULTS Of 126,936 patients who underwent a colonoscopy, 3804 were diagnosed with CRC and defined the index cases. FDRs had an increased risk of CRC (hazard rate ratio [HRR], 1.79; 95% confidence interval [CI],1.59-2.03), as did second-degree relatives (HRR, 1.32; 95% CI, 1.19-1.47) and first cousins (HRR, 1.15; 95% CI, 1.07-1.25), compared with relatives of controls. This risk was greater for FDRs when index patients developed CRC at younger than age 60 years (HRR, 2.11; 95% CI, 1.70-2.63), compared with older than age 60 years (HRR, 1.77; 95% CI, 1.58-1.99). The risk of adenomas (HRR, 1.82; 95% CI, 1.66-2.00) and adenomas with villous histology (HRR, 2.43; 95% CI, 1.96-3.01) also were increased in FDRs. Three percent of CRCs in FDRs would have been missed if the current guidelines, which stratify screening recommendations by the age of the proband, were strictly followed. CONCLUSIONS FDRs, second-degree relatives, and first cousins of patients who undergo colonoscopy and are found to have CRC have a significant increase in the risk of colorectal neoplasia. These data should be considered when establishing CRC screening guidelines for individuals and families.

Replication of the 10q11 and Xp11 Prostate Cancer Risk Variants: Results from a Utah Pedigree-Based Study

A recent genome-wide association study suggested seven new loci as associated with prostate cancer susceptibility. The strongest associated single nucleotide polymorphism (SNP) in each region was identified (rs2660753, rs9364554, rs6465657, rs10993994, rs7931342, rs2735839, rs5945619). We studied these seven SNPs in a replication study consisting of 169 familial prostate cancer cases selected from Utah high-risk prostate cancer pedigrees and 805 controls. We performed subset analyses for aggressive and early-onset prostate cancer. At a nominal significance level, two SNPs were found to be associated with prostate cancer: rs10993994 on chromosome 10q11 [odds ratio (OR), 1.42; 95% confidence interval (95% CI), 1.05-1.90; P = 0.022] and rs5945619 on chromosome Xp11 (OR, 1.54; 95% CI, 1.03-2.31; P = 0.035). Restricting analysis to familial prostate cancer cases with aggressive disease yielded very similar risk estimates at both SNPs. However, subset analysis for familial, early-onset disease indicated highly significant association evidence and substantially higher risk estimates for rs10993994 (OR, 2.20; 95% CI, 1.48-3.27; P < 0.0001). This result suggests that the higher risk estimates from the stage 1 cohort in the original study for rs10993994 may have been due to the early-onset and familial nature of the prostate cancer cases in that cohort. In conclusion, in a small case-control study of prostate cancer cases from Utah high-risk pedigrees, we have significantly replicated association of prostate cancer with rs10993994 (10q11) upon study-wide correction for multiple comparisons. We also nominally replicated the association of prostate cancer with rs5945619 (Xp11). In particular, it seems that the susceptibility locus at 10q11 maybe involved in familial, early-onset disease. (Cancer Epidemiol Biomarkers Prev 2009;18(4):1290–4)

PedGenie: meta genetic association testing in mixed family and case-control designs

Background-PedGenie software, introduced in 2006, includes genetic association testing of cases and controls that may be independent or related (nuclear families or extended pedigrees) or mixtures thereof using Monte Carlo significance testing. Our aim is to demonstrate that PedGenie, a unique and flexible analysis tool freely available in Genie 2.4 software, is significantly enhanced by incorporating meta statistics for detecting genetic association with disease using data across multiple study groups.Methods-Meta statistics (chi-squared tests, odds ratios, and confidence intervals) were calculated using formal Cochran-Mantel-Haenszel techniques. Simulated data from unrelated individuals and individuals in families were used to illustrate meta tests and their empirically-derived p-values and confidence intervals are accurate, precise, and for independent designs match those provided by standard statistical software.Results-PedGenie yields accurate Monte Carlo p-values for meta analysis of data across multiple studies, based on validation testing using pedigree, nuclear family, and case-control data simulated under both the null and alternative hypotheses of a genotype-phenotype association.Conclusion-PedGenie allows valid combined analysis of data from mixtures of pedigree-based and case-control resources. Added meta capabilities provide new avenues for association analysis, including pedigree resources from large consortia and multi-center studies.

Epidemiology and Familial Risk of Synchronous and Metachronous Colorectal Cancer: A Population-Based Study in Utah

BACKGROUND & AIMS Patients diagnosed with colorectal cancer (CRC) are at risk for synchronous and metachronous lesions at the time of diagnosis or during follow-up evaluation. We performed a population-based study to evaluate the rate, predictors, and familial risk for synchronous and metachronous CRC in Utah. METHODS All newly diagnosed cases of CRC between 1980 and 2010 were obtained from the Utah Cancer Registry and linked to pedigrees from the Utah Population Database. RESULTS Of the 18,782 patients diagnosed with CRC, 134 were diagnosed with synchronous CRC (0.71%) and 300 were diagnosed with metachronous CRC (1.60%). The risk for synchronous CRC was significantly higher in men (odds ratio [OR], 1.45; 95% confidence interval [CI], 1.02-2.06) and in patients aged 65 years or older (OR, 1.50; 95% CI, 1.02-2.21). Synchronous CRCs were located more often in the proximal colon (OR, 1.70; 95% CI, 1.20-2.41). First-degree relatives of cases with synchronous (OR, 1.86; 95% CI, 1.37-2.53), metachronous (OR, 2.34; 95% CI, 1.62-3.36), or solitary CRC (OR, 1.75; 95% CI, 1.63-1.88) were at increased risk for developing CRC, compared with relatives of CRC-free individuals. Four percent of first-degree relatives of patients with synchronous or metachronous cancer developed CRC at younger ages than the age recommended for initiating CRC screening (based on familial risk), and therefore would not have been screened. CONCLUSIONS Of patients diagnosed with CRC, 2.3% are found to have synchronous lesions or develop metachronous CRC during follow-up evaluation. Relatives of these patients have a greater risk of CRC than those without a family history of CRC. These results highlight the importance of obtaining a thorough family history and adhering strictly to surveillance guidelines during management of high-risk patients.

hapConstructor: automatic construction and testing of haplotypes in a Monte Carlo framework

Summary: Haplotypes carry important information that can direct investigators towards underlying susceptibility variants, and hence multiple tagging single nucleotide polymorphisms (tSNPs) are usually studied in candidate gene association studies. However, it is often unknown which SNPs should be included in haplotype analyses, or which tests should be performed for maximum power. We have developed a program, hapConstructor, which automatically builds multi-locus SNP sets to test for association in a case-control framework. The multi-SNP sets considered need not be contiguous; they are built based on significance. An important feature is that the missing data imputation is carried out based on the full data, for maximal information and consistency. HapConstructor is implemented in a Monte Carlo framework and naturally extends to allow for significance testing and false discovery rates that account for the construction process and to related individuals. HapConstructor is a useful tool for exploring multi-locus associations in candidate genes and regions. Availability: http://www-genepi.med.utah.edu/Genie Contact: ryan.abo@hsc.utah.edu

Risk of Autoimmunity in EoE and Families: A Population-Based Cohort Study.

Objectives:Recent genome-wide association studies have suggested possible genetic associations between eosinophilic esophagitis (EoE) and genes associated with autoimmunity. No studies to date have looked at potential genetic association of EoE with specific autoimmune diseases by evaluating such diagnoses within family members. Investigate the risk of specific autoimmune disease within EoE probands and their extended family members.Methods:The Utah Population Database offers a unique opportunity to link medical records from over 85% of Utah’s population to genealogy records representing Utah. We searched for associations of specific autoimmune diseases in probands diagnosed with EoE and their extended family members (e.g., first cousins). Comparisons were made to age- and sex-matched controls and their respective families at a 5:1 ratio.Results:Excess risk for multiple autoimmune conditions was detected in subjects with a diagnosis of EoE. Celiac, Crohn’s, ulcerative colitis (UC), rheumatoid arthritis, IgA deficiency, CVID, multiple sclerosis (MS), and Hashimoto’s thyroiditis were found at increased risk in first-degree relatives of EoE subjects. UC, systemic sclerosis, and MS had nominally significant associations within second-degree family members of EoE subjects; and, in reverse analysis, probands and their families with the above three conditions were at an increased risk for EoE suggesting shared genetic factors with EoE.Conclusions:Patients with EoE have an increased risk of multiple autoimmune diseases. Possible shared genetic etiologies were observed between EoE and UC, systemic sclerosis, and MS. Practitioners should be aware of these comorbid associations and query all EoE patients and family members for symptoms of these diseases.

Increased Risk of Colorectal Cancer Among Family Members of All Ages, Regardless of Age of Index Case at Diagnosis.

BACKGROUND & AIMS It is not clear whether familial risk of colorectal cancer (CRC) varies with age of index CRC patients or their relatives. We quantified the risk of CRC in first-degree relatives (FDRs), second-degree relatives, and first-cousin relatives of individuals with CRC, stratified by ages and sexes of index patients and ages of relatives. METHODS CRCs diagnosed between 1980 and 2010 were identified from the Utah Cancer Registry and linked to pedigrees from the Utah Population Database. Age- and sex-matched CRC-free individuals were selected to form the comparison group. CRC risk in relatives was determined by Cox regression analysis. RESULTS Of 18,208 index patients diagnosed with CRC, the highest familial risk was observed in FDRs of index CRC patients who were diagnosed at an age younger than 40 years (hazard ratio [HR], 2.53; 95% confidence interval [CI], 1.7-3.79). However, familial risk was increased in FDRs even when the index case was diagnosed with cancer at an advanced age (>80 years; HR, 1.76; 95% CI, 1.59-1.94). Ages of relatives and ages of index cases of CRC each affected familial cancer risk; the highest risk was found in young relatives (<50 years) of individuals with early-onset CRC (<40 years; HR, 7.0; 95% CI, 2.86-17.09). CONCLUSIONS All relatives of individuals with CRC are at increased risk for this cancer, regardless of the age of diagnosis of the index patient. Although risk is greatest among young relatives of early-onset CRC cases, relatives of patients diagnosed at advanced ages also have an increased risk.

Familial colorectal cancer risk by subsite of primary cancer: a population-based study in Utah.

Familial occurrence is common in colorectal cancer (CRC), but whether this increased familial risk differs by colonic subsite of the index patients CRC is not well understood.

Meta-genetic association of rheumatoid arthritis and PTPN22 using PedGenie 2.1

PedGenie beta version 2.1 is a unique, flexible, and easily implemented analysis software tool that is enhanced significantly by incorporation of meta-statistics to allow valid combined analysis of multiple studies, including mixtures of family-based and independent resources, in the detection of genetic association with common disease. Genetic Analysis Workshop 15 Problem 2 data, provided by the North American Rheumatoid Arthritis Consortium, were used to demonstrate PedGenie 2.1 meta-association testing of variants in the PTPN22 gene and rheumatoid arthritis across multiple resources containing both family-based and independent individuals. Our findings are generally consistent with previous reports for a panel of 14 single-nucleotide polymorphism (SNP) markers, including functional coding SNP R620W, in which the minor allele conferred a significant two-fold increased risk. More power to detect associations was achieved in certain analyses by using extra family-based samples, rather than restricting analyses to single cases randomly selected from each pedigree.