Kerry Rowe

Predisposition locus for major depression at chromosome 12q22-12q23.2

Major depression disorder is a common psychiatric disease with a major economic impact on society. In many cases, no effective treatment is available. The etiology of major depression is complex, but it is clear that the disease is, to a large extent, determined genetically, especially among individuals with a familial history of major depression, presumably through the involvement of multiple predisposition genes in addition to an environmental component. As a first step toward identification of chromosomal loci contributing to genetic predisposition to major depression, we have conducted a genomewide scan by using 628 microsatellite markers on 1,890 individuals from 110 Utah pedigrees with a strong family history of major depression. We identified significant linkage to major depression in males at marker D12S1300 (multipoint heterogeneity LOD score 4.6; P=.00003 after adjustment for multiple testing). With additional markers, the linkage evidence became highly significant, with the multipoint heterogeneity LOD score at marker D12S1706 increasing to 6.1 (P=.0000007 after adjustment for multiple testing). This study confirms the presence of one or more genes involved in psychiatric diseases on the q arm of chromosome 12 and provides strong evidence for the existence of a sex-specific predisposition gene to major depression at 12q22-q23.2.

Genome-wide linkage analyses of extended Utah pedigrees identifies loci that influence recurrent, early-onset major depression and anxiety disorders

Major depressive disorder (MDD) is a common, clinically heterogeneous disorder often found comorbid with other disorders. We studied recurrent, early‐onset MDD (MDD‐RE) and anxiety disorders in combination to define powerful phenotypes for genetic study. We used 87 large, extended Utah pedigrees to investigate linkage to 3 phenotypes: “MDD‐RE;” “MDD‐RE or anxiety;” and “MDD‐RE and anxiety;” where in the latter definition the disorders must appear comorbid within an individual. Pedigrees ranged in size from 2 to 6 generations and contained 3 to 42 individuals affected with MDD or anxiety (718 total). In primary analyses, we identified three regions with at least suggestive genome‐wide evidence for linkage on chromosomes 3centr, 7p, and 18q. Both 7p and 18q are replication findings for related phenotypes. The best linkage evidence was for a novel locus at 3p12.3‐q12.3 (LOD = 3.88, “MDD‐RE or anxiety”) and 18q21.33‐q22.2 (LOD = 3.75, “MDD‐RE and anxiety”), a well‐established susceptibility locus for bipolar disorder. In our secondary sex‐specific analyses, we identified two further regions of interest on chromosomes 4q and 15q. Using linked pedigrees, we localized 3centr and 18q to 9.8 and 12.2 cM, respectively, with potential for further localization with the addition of markers in specific pedigrees. Our success in replication and novel locus identification illustrates the utility of large extended pedigrees for common disorders, such as MDD. Further, it supports the hypothesis that MDD and anxiety disorders have over‐lapping genetic etiologies and suggests that comorbid diagnoses may be useful in defining more genetically homogeneous forms of MDD for linkage mapping.

Evaluation of record linkage between a large healthcare provider and the Utah Population Database

OBJECTIVE Electronically linked datasets have become an important part of clinical research. Information from multiple sources can be used to identify comorbid conditions and patient outcomes, measure use of healthcare services, and enrich demographic and clinical variables of interest. Innovative approaches for creating research infrastructure beyond a traditional data system are necessary. MATERIALS AND METHODS Records from a large healthcare systems enterprise data warehouse (EDW) were linked to a statewide population database, and a master subject index was created. The authors evaluate the linkage, along with the impact of missing information in EDW records and the coverage of the population database. The makeup of the EDW and population database provides a subset of cancer records that exist in both resources, which allows a cancer-specific evaluation of the linkage. RESULTS About 3.4 million records (60.8%) in the EDW were linked to the population database with a minimum accuracy of 96.3%. It was estimated that approximately 24.8% of target records were absent from the population database, which enabled the effect of the amount and type of information missing from a record on the linkage to be estimated. However, 99% of the records from the oncology data mart linked; they had fewer missing fields and this correlated positively with the number of patient visits. DISCUSSION AND CONCLUSION A general-purpose research infrastructure was created which allows disease-specific cohorts to be identified. The usefulness of creating an index between institutions is that it allows each institution to maintain control and confidentiality of their own information.

Risk of colorectal cancer and adenomas in the families of patients with adenomas: A population-based study in Utah

Guidelines recommend that individuals with a first‐degree relative (FDR) diagnosed with colorectal cancer (CRC) or advanced adenoma before age 60 years should undergo colonoscopy starting at age 40 years. The authors quantified the risk of adenomas and CRC in FDRs, second‐degree relatives (SDRs), and third‐degree relatives (TDRs) of patients diagnosed with adenomas and advanced adenomas.

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.

Familial clustering of endometrial cancer in a well-defined population

OBJECTIVE Using a genealogical database, we examined risk of endometrial cancer among family members of individuals with endometrial cancer. METHODS We identified endometrial cancer cases in the Utah Population Database (UPDB), a computerized archive of genealogy data linked to the Utah Cancer Registry. We tested for excess relatedness and estimated relative risks (RR) among first-, second-, and third-degree relatives of endometrial cancer cases and stratified analyses by tumor histology and body mass index (BMI). RESULTS We identified 3911 cases; 3546 were Type I cancers and 365 Type II cancers. The RR for all endometrial cancer cases and for cases with type I histology was significantly increased for first-, second-, and third-degree relatives. An almost three-fold risk was observed among first-degree relatives of individuals with Type I cancers and a 2.24-fold risk among second-degree relatives of Type I morbidly obese cases. The magnitude of endometrial cancer risk among relatives appeared to increase with case BMI. CONCLUSIONS The elevated risks for endometrial cancer among first-, second-, and third-degree relatives support a genetic contribution to predisposition to endometrial cancer. The increased risk appears to be limited to Type I endometrial cancer. We observed increased risks for endometrial cancer among relatives of obese and morbidly obese Type I cases, which may be indicative of a synergistic relationship between underlying genetic propensity and shared environment. This study quantifies risk of developing cancer among relatives of patients with disease and provides the basis for further analysis of high risk pedigrees and gene identification for genetic etiologies of endometrial cancer.

Significant evidence for linkage to chromosome 5q13 in a genome-wide scan for asthma in an extended pedigree resource

Asthma is a multifactorial disease with undetermined genetic factors. We performed a genome-wide scan to identify predisposition loci for asthma. The asthma phenotype consisted of physician-confirmed presence or absence of asthma symptoms. We analyzed 81 extended Utah pedigrees ranging from three to six generations, including 742 affected individuals, ranging from 2 to 40 per pedigree. We performed parametric multipoint linkage analyses with dominant and recessive models. Our analysis revealed genome-wide significant evidence of linkage to region 5q13 (log of the odds ratio (LOD)=3.8, recessive model), and suggestive evidence for linkage to region 6p21 (LOD=2.1, dominant model). Both the 5q13 and 6p21 regions indicated in these analyses have been previously identified as regions of interest in other genome-wide scans for asthma-related phenotypes. The evidence of linkage at the 5q13 region represents the first significant evidence for linkage on a genome-wide basis for this locus. Linked pedigrees localize the region to approximately between 92.3–105.5 Mb.

Aging-Related Disease Risks among Young Thyroid Cancer Survivors

Background: Thyroid cancer is the most rapidly increasing cancer in the United States, affects a young population, has high survival, and is one of the most common cancers in people under age 40. The aim of this study was to examine the risks of aging-related diseases in a statewide sample of thyroid cancer survivors who were diagnosed <40 years compared with those diagnosed ≥40 and a cancer-free sample. Methods: Thyroid cancer survivors diagnosed 1997 to 2012 were matched to up to 5 cancer-free individuals on birth year, sex, birth state, using the statewide Utah Population Database. Medical records were used to identify disease diagnoses stratified over three time periods: 1 to 5, >5 to 10, and 10+ years after cancer diagnosis. Cox proportional hazards models were used to estimate hazard ratios with adjustment on matching factors, race, body mass index, and Charlson Comorbidity Index. Results: There were 3,706 thyroid cancer survivors and 15,587 matched cancer-free individuals (1,365 cases diagnosed <40 years old). Both age groups had increased risks for multiple circulatory health conditions 1 to 5 years after cancer diagnosis compared with cancer-free individuals. Survivors <40 had a higher risk of hypertension, cardiomyopathy, and nutritional deficiencies. Conclusions: Increased risks for diseases associated with aging were observed for both age groups, with younger thyroid cancer survivors having higher risks for select diseases. Impact: As thyroid cancer survivors in this study were found to have increased risks for aging-related diseases, future studies are needed to assess what can be done to reduce the increased risks of these long-term health effects. Cancer Epidemiol Biomarkers Prev; 26(12); 1695–704. ©2017 AACR.

Risk Factors for Cardiovascular Disease among Thyroid Cancer Survivors: Findings from the Utah Cancer Survivors Study.

Context Thyroid cancer survivors are at high risk of developing multiple cardiac and vascular conditions as consequence of cancer diagnosis and treatment. However, it is still unclear how the baseline and prognostic factors, as well as cancer treatments, play a role in increasing cardiac and vascular disease risk among thyroid cancer survivors. Objective To investigate the association between potential risk factors, treatment effects, and cardiovascular disease (CVD) outcomes in thyroid cancer survivors. Design, Setting, Patients Primary thyroid cancer survivors, diagnosed from 1997 to 2012 (n = 3822), were identified using the statewide Utah Population Database. The medical records were used to ascertain information on risk factors and CVD outcomes. Cox proportional hazards models were used to assess the risk of CVD with baseline demographic data and clinical factors. Results Among thyroid cancer survivors, age and year at cancer diagnosis, cancer stage, sex, baseline body mass index, baseline comorbidities, and TSH suppression therapy were significantly associated with CVD risk 1 to 5 years after cancer diagnosis. Patients who were male, overweight or obese, older at cancer diagnosis, and diagnosed with cancer since 2005 had an increased risk of CVD compared with patients who were female, had a normal body mass index, were younger at cancer diagnosis, and diagnosed with cancer from 1997 to 1999. Administration of TSH suppression therapy, distant metastases at cancer diagnosis, and a higher Charlson comorbidity index score were associated with an increased CVD risk among thyroid cancer survivors. Conclusions Our findings suggest that examining the effect of thyroid cancer diagnosis, cancer treatment, and demographic characteristics on the risk of CVD is critical.

Long-term Cardiovascular Outcomes Among Endometrial Cancer Survivors in a Large, Population-Based Cohort Study

Background Endometrial cancer is the second most common cancer among female cancer survivors in the United States. Cardiovascular disease is the leading cause of death among endometrial cancer survivors. Studies that examine long-term cardiovascular outcomes among endometrial cancer survivors are critical. Methods Cohorts of 2648 endometrial cancer survivors diagnosed between 1997 and 2012 and 10 503 age-matched women from the general population were identified. Cardiovascular disease diagnoses were identified from electronic medical records and statewide ambulatory surgery and statewide inpatient data. Cox regression models were used to estimate hazard ratios (HRs) at one to five years, more than five to 10 years, and more than 10 years after cancer diagnosis. Results Between one and five years after diagnosis, increased cardiovascular risks among endometrial cancer survivors were observed for phlebitis, thrombophlebitis, and thromboembolism (HR = 2.07, 99% confidence interval [CI] = 1.57 to 2.72), pulmonary heart disease (HR = 1.74, 99% CI = 1.26 to 2.40), and atrial fibrillation (HR = 1.50, 99% CI = 1.07 to 2.11). At more than five to 10 years, some elevated risk persisted for cardiovascular diseases. Compared with patients who had surgery, patients who additionally had radiation therapy and/or chemotherapy were at increased risk for heart and circulatory system disorders between one and five years after cancer diagnosis. Older age and obesity were also risk factors for hypertension and heart disease among endometrial cancer survivors. Conclusions Endometrial cancer survivors are at higher risk for various adverse long-term cardiovascular outcomes compared with women from the general population. This study suggests that increased monitoring for cardiovascular diseases may be necessary for endometrial cancer patients for 10 years after cancer diagnosis.