Whole-genome sequencing analysis of suicide deaths integrating brain-regulatory eQTLs data to identify risk loci and genes.

Recent large-scale genome-wide association studies (GWAS) have started to identify potential genetic risk loci associated with risk of suicide; however, a large portion of suicide-associated genetic factors affecting gene expression remain elusive. Dysregulated gene expression, not assessed by GWAS, may play a significant role in increasing the risk of suicide death. We performed the first comprehensive genomic association analysis prioritizing brain expression quantitative trait loci (eQTLs) within regulatory regions in suicide deaths from the Utah Suicide Genetic Risk Study (USGRS). 440,324 brain-regulatory eQTLs were obtained by integrating brain eQTLs, histone modification ChIP-seq, ATAC-seq, DNase-seq, and Hi-C results from publicly available data. Subsequent genomic analyses were conducted in whole-genome sequencing (WGS) data from 986 suicide deaths of non-Finnish European (NFE) ancestry and 415 ancestrally matched controls. Additional independent USGRS suicide deaths with genotyping array data (n = 4657) and controls from the Genome Aggregation Database were explored for WGS result replication. One significant eQTL locus, rs926308 (p = 3.24e-06), was identified. The rs926308-T is associated with lower expression of RFPL3S, a gene important for neocortex development and implicated in arousal. Gene-based analyses performed using Sherlock Bayesian statistical integrative analysis also detected 20 genes with expression changes that may contribute to suicide risk. From analyzing publicly available transcriptomic data, ten of these genes have previous evidence of differential expression in suicide death or in psychiatric disorders that may be associated with suicide, including schizophrenia and autism (ZNF501, ZNF502, CNN3, IGF1R, KLHL36, NBL1, PDCD6IP, SNX19, BCAP29, and ARSA). Electronic health records (EHR) data was further merged to evaluate if there were clinically relevant subsets of suicide deaths associated with genetic variants. In summary, our study identified one risk locus and ten genes associated with suicide risk via gene expression, providing new insight into possible genetic and molecular mechanisms leading to suicide.

Analysis of acute extremity compartment syndrome using a genealogic population database.

INTRODUCTION: Acute extremity compartment syndrome ("CS") is an under-researched, highly morbid condition affecting trauma populations. The purpose of this study was to analyze incidence rates and risk factors for extremity compartment syndrome using a high-quality population database. Additionally, we evaluated heritable risk for CS using available genealogic data. We hypothesized that diagnosis of extremity compartment syndrome would demonstrate heritability. MATERIALS AND METHODS: Adult patients with fractures of the tibia, femur, and upper extremity were retrospectively identified by ICD-9, ICD-10, and CPT codes from 1996 to 2020 in a statewide hospital database. Exposed and unexposed cohorts were created based on a diagnosis of CS. Available demographic data were analyzed to determine risk factors for compartment syndrome using logistic regression. Mortality risk at the final follow-up was evaluated using Cox proportional hazard modeling. Patients with a diagnosis of CS were matched with those without a diagnosis for heritability analysis. RESULTS: Of 158,624 fractures, 931 patients were diagnosed with CS. Incidence of CS was 0.59% (tibia 0.83%, femur 0.31%, upper extremity 0.27%). Male sex (78.1% vs. 46.4%; p < 0.001; RR = 3.24), younger age at fracture (38.8 vs. 48.0 years; p < 0.001; RR = 0.74), Medicaid enrollment (13.2% vs. 9.3%; p < 0.001; RR = 1.58), and smoking (41.1% vs. 31.1%; p < 0.001; RR 1.67) were significant risk factors for CS. CS was associated with mortality (RR 1.61, p < 0.001) at mean follow-up 8.9 years in the CS cohort. No significant heritable risk was found for diagnosis of CS. CONCLUSIONS: Without isolating high-risk fractures, rates of CS are lower than previously reported in the literature. Male sex, younger age, smoking, and Medicaid enrollment were independent risk factors for CS. CS increased mortality risk at long-term follow-up. No heritable risk was found for CS. LEVEL OF EVIDENCE: III.

Surveillance Imaging with PET/CT and CT and/or MRI for Head and Neck Cancer and Mortality: A Population-based Study.

Background To the knowledge of the authors, no strong evidence supports surveillance imaging in patients with head and neck cancer (HNC). Purpose To investigate the association between surveillance imaging and mortality using a population-based study design with statewide cancer registry data, all-payer claims data, and health care facility data. Materials and Methods The retrospective population-based study identified patients with HNC diagnosed between January 2012 and December 2017. Current Procedural Terminology codes were used to search surveillance imaging procedures. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% CIs for mortality with adjustment for sex, ethnicity, age, health insurance status, cancer site, stage, and treatment. Results The study identified 1004 patients (mean age, 61 years ± 12 [SD]; 753 men), including 902 patients with squamous cell carcinoma (SCC) HNC and 102 patients with non-SCC. The effect of imaging on mortality among patients with SCC was not statistically significant when the entire sample was analyzed (HR, 0.76; 95% CI: 0.57, 1.02; P = .07). However, in stratified analyses by cancer stage, surveillance imaging was associated with lower mortality among patients with SCC for regionalized cancer stage (HR, 0.55; 95% CI: 0.36, 0.83; P = .005) and distant cancer stage (HR, 0.40; 95% CI: 0.19, 0.83; P = .01). Among patients with non-SCC, surveillance imaging was associated with lower mortality versus no surveillance imaging (HR, 0.19; 95% CI: 0.04, 0.94; P = .04). PET/CT was associated with lower mortality for patients with SCC (HR, 0.29; 95% CI: 0.09, 0.94; P = .04), and CT and/or MRI was associated with lower mortality for patients with non-SCC (HR, 0.11; 95% CI: 0.01, 0.94; P = .04). Conclusion Surveillance imaging was associated with lower mortality among patients with head and neck squamous cell carcinoma with regionalized or distant disease. The surveillance imaging protective association was observed up to 2 years after treatment completion. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Branstetter in this issue.

Contributions of cancer treatment, comorbidities, and obesity to aging-related disease risks among non-Hodgkin lymphoma survivors.

PURPOSE: It is unknown whether cancer treatment contributes more to long-term disease risk than lifestyle factors and comorbidities among B-cell non-Hodgkin lymphoma (B-NHL) survivors. METHODS: B-NHL survivors were identified in the Utah Cancer Registry from 1997 to 2015. Population attributable fractions (PAF) were calculated to assess the role of clinical and lifestyle factors for six cardiovascular, pulmonary, and renal diseases. RESULTS: Cancer treatment contributed to 11% of heart and pulmonary conditions and 14.1% of chronic kidney disease. Charlson Comorbidity Index (CCI) at baseline contributed to all six diseases with a range of 9.9% of heart disease to 26.5% of chronic kidney disease. High BMI at baseline contributed to 18.4% of congestive heart failure and 7.9% of pneumonia, while smoking contributed to 4.8% of COPD risk. CONCLUSION: Cancer treatment contributed more to heart disease, COPD, and chronic kidney disease than lifestyle factors and comorbidities among B-NHL survivors. High BMI at baseline contributed more to congestive heart failure and pneumonia than cancer treatment, whereas smoking at baseline was not a major contributor in this B-NHL survivor cohort. Baseline comorbidities consistently demonstrated high attributable risks for these diseases, demonstrating a strong association between preexisting comorbidities and aging-related disease risks.

Long-term maternal mortality risk following spontaneous preterm birth: A retrospective cohort study.

OBJECTIVE: To determine whether women with spontaneous preterm birth (PTB) have increased risks for long-term mortality. DESIGN: Retrospective cohort. SETTING: Births in Utah between 1939 and 1977. POPULATION: We included women with a singleton live birth ≥20 weeks who survived at least 1 year following delivery. We excluded those who had never lived in Utah, had improbable birthweight/gestational age combinations, underwent induction (except for preterm membrane rupture) or had another diagnosis likely to cause PTB. METHODS: Exposed women had ≥1 spontaneous PTB between 20+0 weeks and 37+0 weeks. Women with >1 spontaneous PTB were included only once. Unexposed women had all deliveries at or beyond 38+0 weeks. Exposed women were matched to unexposed women by birth year, infant sex, maternal age group and infant birth order. Included women were followed up to 39 years after index delivery. MAIN OUTCOME MEASURES: Overall and cause-specific mortality risks were compared using Cox regression. RESULTS: We included 29 048 exposed and 57 992 matched unexposed women. There were 3551 deaths among exposed (12.2%) and 6013 deaths among unexposed women (10.4%). Spontaneous PTB was associated with all-cause mortality (adjusted hazard ratio [aHR] 1.26, 95% confidence interval [CI] 1.21-1.31), death from neoplasms (aHR 1.10, 95% CI 1.02-1.18), circulatory disease (aHR 1.35, 95% CI 1.25-1.46), respiratory disease (aHR 1.73, 95% CI 1.46-2.06), digestive disease (aHR 1.33, 95% CI 1.12-1.58), genito-urinary disease (aHR 1.60, 95% CI 1.15-2.23) and external causes (aHR 1.39, 95% CI 1.22-1.58). CONCLUSIONS: Spontaneous PTB is associated with modestly increased risks for all-cause and some cause-specific mortality.

Familial aggregation of stillbirth: A pedigree analysis of a matched case-control study.

OBJECTIVE: To determine whether stillbirth aggregates in families and quantify its familial risk using extended pedigrees. DESIGN: State-wide matched case-control study. SETTING: Utah, United States. POPULATION: Stillbirth cases (n = 9404) and live birth controls (18 808) between 1978 and 2019. METHODS: Using the Utah Population Database, a population-based genealogical resource linked with state fetal death and birth records, we identified high-risk pedigrees with excess familial aggregation of stillbirth using the Familial Standardised Incidence Ratio (FSIR). Stillbirth odds ratio (OR) for first-degree relatives (FDR), second-degree relatives (SDR) and third-degree relatives (TDR) of parents with a stillbirth (affected) and live birth (unaffected) were estimated using logistic regression models. MAIN OUTCOME MEASURES: Familial aggregation estimated using FSIR, and stillbirth OR estimated for FDR, SDR and TDR of affected and unaffected parents using logistic regression models. RESULTS: We identified 390 high-risk pedigrees with evidence for excess familial aggregation (FSIR ≥2.00; P-value <0.05). FDRs, SDRs and TDRs of affected parents had 1.14-fold (95% confidence interval [CI]: 1.04-1.26), 1.22-fold (95% CI 1.11-1.33) and 1.15-fold (95% CI 1.08-1.21) higher stillbirth odds compared with FDRs, SDRs and TDRs of unaffected parents, respectively. Parental sex-specific analyses showed male FDRs, SDRs and TDRs of affected fathers had 1.22-fold (95% CI 1.02-1.47), 1.38-fold (95% CI 1.17-1.62) and 1.17-fold (95% CI 1.05-1.30) higher stillbirth odds compared with those of unaffected fathers, respectively. FDRs, SDRs and TDRs of affected mothers had 1.12-fold (95% CI 0.98-1.28), 1.09-fold (95% CI 0.96-1.24) and 1.15-fold (95% CI 1.06-1.24) higher stillbirth odds compared with those of unaffected mothers, respectively. CONCLUSIONS: We provide evidence for familial aggregation of stillbirth. Our findings warrant investigation into genes associated with stillbirth and underscore the need to design large-scale studies to determine the genetic architecture of stillbirth.

Interpregnancy Body Mass Index Change and Offspring Mortality Risk following the Second Pregnancy.

OBJECTIVE: The aim of the study is to examine the impact of maternal interpregnancy body mass index (BMI) change on subsequent offspring mortality risk. STUDY DESIGN: This is a retrospective cohort study of women who had two consecutive live singleton deliveries of at least 20 weeks' gestation from the Utah Population Database. Our exposure was defined as interpregnancy BMI change from the date of first delivery to the conception date of subsequent pregnancy. We categorized BMI change as: < - 1, -1 to 0, 0 to <1 (reference), 1 to 2, 2 to 4, ≥4 kg/m2. Our primary outcome was all-cause age-specific mortality during four time periods: neonatal (≤28 days), infant (29 days to <1 year old), childhood ((≥1 to <5 years old), and late childhood (5 to <18 years old). We also examined mortality specifically attributed to congenital anomalies. Analyses used Cox proportional hazard models stratified by full term (≥37 weeks) and preterm (<37 weeks) deliveries. All models were adjusted for relevant confounders. RESULTS: Of 266,752 women, among full-term deliveries, women with a BMI increase of 4 kg/m2 or more had an increased risk of neonatal mortality in their subsequent pregnancy (hazard ratio or HR = 1.72, 95% confidence interval or CI: 1.23-2.41) Women who lost 1 kg/m2 or more between deliveries also had increased neonatal mortality (HR = 1.46, 95% CI: 1.04-2.05). There were no differences in infant, early, or late childhood mortality by interpregnancy BMI change. Maternal interpregnancy interval weight loss of 1 kg/m2 or more and weight gain of ≥4 kg/m2 also had increased risk of mortality associated with congenital anomalies or conditions arising during the neonatal period following their subsequent delivery. CONCLUSION: Women with significant interpregnancy weight gain and modest weight loss have a significant increased risk of neonatal mortality following their subsequent pregnancy. KEY POINTS: · Significant weight gain between deliveries increases the risk of neonatal death.. · Modest weight loss between deliveries increases the risk of neonatal death.. · This risk may be partially explained by increased risk of congenital malformations..

Cardiovascular disease risk in long-term breast cancer survivors: A population-based cohort study.

BACKGROUND: Breast cancer survival is increasing, making late effects such as cardiovascular disease (CVD) more relevant. The purpose of this study was to evaluate incident CVD following breast cancer diagnosis among long-term survivors and to investigate possible risk factors for CVD. METHODS: A population-based cohort of 6641 breast cancer survivors diagnosed between 1997 and 2009 who survived at least 10 years was identified within the Utah Cancer Registry. In addition, 36,612 cancer-free women from the general population, matched by birth year and state, were identified within the Utah Population Database. Cox proportional hazards models were used to calculate CVD hazard ratios (HRs) for >10 to 15 and >15 years. RESULTS: Long-term breast cancer survivors had an increased risk of newly diagnosed diseases of the circulatory system (HR, 1.32; 99% confidence interval [CI], 1.00-1.75) from 10 to 15 years following cancer diagnosis compared with the general population. No increased CVD risks were observed after 15 years. Breast cancer survivors with Charlson Comorbidity Index score ≥2 had a significantly higher risk of diseases of the circulatory system (HR, 2.64; 95% CI, 1.08-6.45) beyond 10 years following breast cancer diagnosis. Similarly, older age, obesity, lower education, and family history of CVD and breast cancer were risk factors for heart and circulatory system diseases among long-term breast cancer survivors. CONCLUSION: Risk of CVD compared to the general population was moderate among this cohort of long-term breast cancer survivors between 10 to 15 years since cancer diagnosis. Awareness of CVD risks is important for breast cancer survivors.

Mental health disorders are more common in patients with Hodgkin lymphoma and may negatively impact overall survival.

BACKGROUND: Long-term mental health outcomes were characterized in patients who were diagnosed with Hodgkin lymphoma (HL), and risk factors for the development of mental health disorders were identified. METHODS: Patients who were diagnosed with HL between 1997 and 2014 were identified in the Utah Cancer Registry. Each patient was matched with up to five individuals from a general population cohort identified within the Utah Population Database, a unique source of linked records that includes patient and demographic data. RESULTS: In total, 795 patients who had HL were matched with 3575 individuals from the general population. Compared with the general population, patients who had HL had a higher risk of any mental health diagnosis (hazard ratio, 1.77; 95% confidence interval, 1.57-2.00). Patients with HL had higher risks of anxiety, depression, substance-related disorders, and suicide and intentional self-inflicted injuries compared with the general population. The main risk factor associated with an increased risk of being diagnosed with mental health disorders was undergoing hematopoietic stem cell transplantation, with a hazard ratio of 2.06 (95% confidence interval, 1.53-2.76). The diagnosis of any mental health disorder among patients with HL was associated with a detrimental impact on overall survival; the 10-year overall survival rate was 70% in patients who had a mental health diagnosis compared with 86% in those patients without a mental health diagnosis (p < .0001). CONCLUSIONS: Patients who had HL had an increased risk of various mental health disorders compared with a matched general population. The current data illustrate the importance of attention to mental health in HL survivorship, particularly for patients who undergo therapy with hematopoietic stem cell transplantation.

Geographic Proximity of Family Members and Healthcare Utilization After Complex Surgical Procedures.

OBJECTIVE: We sought to determine the relationship between a patient's proximal familial social support, defined as the geographic proximity of family members, and healthcare utilization after complex cardiovascular and oncologic procedures. BACKGROUND: Social support mechanisms are increasingly identified as modifiable risk factors for healthcare utilization. METHODS: We performed a retrospective cohort study of 60,895 patients undergoing complex cardiovascular procedures or oncologic procedures. We defined healthcare utilization outcomes as 30-day all-cause readmission unplanned readmission, nonindex hospital readmission, index hospital length of stay, and home discharge disposition. For each patient, we aggregated the number of first-degree relatives (FDR) living within 30 miles of the patient's home address at the time of the surgical procedure into the following categories: 0 to 1, 2 to 3, 4 to 5, 6+ FDRs. We developed hierarchical multivariable regression models to determine the relationship between the number of FDR living within 30 miles of the patient and the healthcare utilization outcomes. RESULTS: Compared with patients with 0 to 1 FDRs, patients with 6+ FDRs living in close proximity had significantly lower rates of all-cause readmission (12.1% vs 13.5%, P <0.001), unplanned readmission (10.9% vs 12.0%, P =0.001), nonindex readmission (2.6% vs 3.2%, P =0.003); higher rates of home discharge (88.0% vs 85.3%, P <0.001); and shorter length of stay (7.3 vs 7.5 days, P =0.02). After multivariable adjustment, a larger number of FDRs living within 30 miles of the patient was significantly associated with a lower likelihood of all-cause readmission ( P <0.001 for trend), 30-day unplanned readmission ( P <0.001), nonindex readmission ( P <0.001); higher likelihood of home discharge ( P <0.001); and shorter index length of stay ( P <0.001). CONCLUSIONS: The geographic proximity of family members is significantly associated with decreased healthcare utilization after complex cardiovascular and oncologic surgical procedures.

Sexual dysfunction among gynecologic cancer survivors in a population-based cohort study.

Treatment for gynecologic cancer is associated with sexual dysfunction, which may present during and/or after treatment. The aim of this study was to investigate the risk of sexual dysfunction among gynecologic cancer survivors compared to cancer-free women in a population-based cohort study. We identified a cohort of 4863 endometrial, ovarian, and cervical cancer survivors diagnosed between 1997 and 2012 in the Utah Cancer Registry. Up to five cancer-free women were matched to cancer survivors (N = 22,693). We used ICD-9 codes to identify sexual dysfunction. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for sexual dysfunction with adjustment for potential confounders. Approximately 6.6% of gynecologic cancer survivors had sexual dysfunction diagnoses 1-5 years after cancer diagnosis. Gynecologic cancer survivors had higher risks of overall sexual dysfunction (HR: 2.51, 95% CI: 2.16, 2.93), dyspareunia (HR: 3.27, 95% CI: 2.63, 4.06), and vaginal dryness (HR: 2.63, 95% CI: 2.21, 3.12) compared to a general population of women, 1-5 years after cancer diagnosis. Sexual dysfunction was associated with advance cancer stage (HRRegional vs. Localized: 1.61, 95% CI: 1.19, 2.31), radiation therapy (HR: 1.73, 95% CI: 1.29, 2.31), and chemotherapy (HR: 1.80, 95% CI: 1.30, 2.50). This large cohort study confirms that there is an increased risk of sexual dysfunction among gynecologic cancer survivors when compared to the general population. Further investigation is needed to address the risk factors for sexual dysfunction and to improve patient-provider communication, diagnosis, documentation, and treatment of sexual dysfunction among gynecologic cancer survivors.

The Vertical Rectus Abdominis Myocutaneous Flap to Manage Vaginal Evisceration.

BACKGROUND: Pelvic organ prolapse (POP) is a significant issue requiring surgical correction in 19% of the female population by age 85 years. Complications of POP, especially in women who have undergone hysterectomy, include vaginal evisceration-a serious complication that carries high morbidity and mortality rates. Rarely, vaginal evisceration occurs after colpocleisis. CASE: A 69-year-old female with recurrent vaginal evisceration following colpocleisis underwent surgical repair using a vertical rectus abdominis myocutaneous (VRAM) flap. CONCLUSION: Recurrent cases of POP and vaginal evisceration that are refractory to conventional treatment require consideration of novel management options. To our knowledge, this is the first case using a VRAM flap for the management of vaginal evisceration.

Extended familial risk of suicide death is associated with younger age at death and elevated polygenic risk of suicide.

Suicide accounts for >800,000 deaths annually worldwide; prevention is an urgent public health issue. Identification of risk factors remains challenging due to complexity and heterogeneity. The study of suicide deaths with increased extended familial risk provides an avenue to reduce etiological heterogeneity and explore traits associated with increased genetic liability. Using extensive genealogical records, we identified high-risk families where distant relatedness of suicides implicates genetic risk. We compared phenotypic and polygenic risk score (PRS) data between suicides in high-risk extended families (high familial risk (HFR), n = 1,634), suicides linked to genealogical data not in any high-risk families (low familial risk (LFR), n = 147), and suicides not linked to genealogical data with unknown familial risk (UFR, n = 1,865). HFR suicides were associated with lower age at death (mean = 39.34 years), more suicide attempts, and more PTSD and trauma diagnoses. For PRS tests, we included only suicides with >90% European ancestry and adjusted for residual ancestry effects. HFR suicides showed markedly higher PRS of suicide death (calculated using cross-validation), supporting specific elevation of genetic risk of suicide in this subgroup, and also showed increased PRS of PTSD, suicide attempt, and risk taking. LFR suicides were substantially older at death (mean = 49.10 years), had fewer psychiatric diagnoses of depression and pain, and significantly lower PRS of depression. Results suggest extended familiality and trauma/PTSD may provide specificity in identifying individuals at genetic risk for suicide death, especially among younger ages, and that LFR of suicide warrants further study regarding the contribution of demographic and medical risks.

Genome-wide significant regions in 43 Utah high-risk families implicate multiple genes involved in risk for completed suicide.

Suicide is the 10th leading cause of death in the United States. Although environment has undeniable impact, evidence suggests that genetic factors play a significant role in completed suicide. We linked a resource of ~ 4500 DNA samples from completed suicides obtained from the Utah Medical Examiner to genealogical records and medical records data available on over eight million individuals. This linking has resulted in the identification of high-risk extended families (7-9 generations) with significant familial risk of completed suicide. Familial aggregation across distant relatives minimizes effects of shared environment, provides more genetically homogeneous risk groups, and magnifies genetic risks through familial repetition. We analyzed Illumina PsychArray genotypes from suicide cases in 43 high-risk families, identifying 30 distinct shared genomic segments with genome-wide evidence (p = 2.02E-07-1.30E-18) of segregation with completed suicide. The 207 genes implicated by the shared regions provide a focused set of genes for further study; 18 have been previously associated with suicide risk. Although PsychArray variants do not represent exhaustive variation within the 207 genes, we investigated these for specific segregation within the high-risk families, and for association of variants with predicted functional impact in ~ 1300 additional Utah suicides unrelated to the discovery families. None of the limited PsychArray variants explained the high-risk family segregation; sequencing of these regions will be needed to discover segregating risk variants, which may be rarer or regulatory. However, additional association tests yielded four significant PsychArray variants (SP110, rs181058279; AGBL2, rs76215382; SUCLA2, rs121908538; APH1B, rs745918508), raising the likelihood that these genes confer risk of completed suicide.

Are paternal or grandmaternal age associated with higher probability of trisomy 21 in offspring? A population-based, matched case-control study, 1995-2015.

BACKGROUND: Fetal aneuploidy risk increases with maternal age, but the majority of pregnancies complicated by trisomy 21 occur in younger women. It has been suggested that grandmaternal and/or paternal age may also play a role. OBJECTIVES: To assess the association between grandmaternal and paternal age and trisomy 21. METHODS: For the grandmaternal assessments, we included all offspring with trisomy 21 in a statewide birth defects surveillance system (1995-2015) that could be linked to 3-generation matrilineal pedigrees in the Utah Population Database. Ten sex/birth year-matched controls were selected for each case (770 cases and 7700 controls). For the paternal assessments, our cohort included all trisomy 21 cases (1995-2015) where both the mother and father resided in Utah at the time of birth (1409 cases and 14 090 controls). Ages were categorised by 5-year intervals (reference: 25-29 years). Conditional logistic regression, adjusting for potential confounding factors, was used to model the association between grandmaternal and paternal age and trisomy 21. RESULTS: No association between grandmaternal age and trisomy 21 was detected, whether age was assessed continuously (adjusted odds ratio [OR] 1.01, 95% confidence interval [CI] 0.98, 1.03) or categorically after adjusting for grandmaternal and grandpaternal race/ethnicity and grandpaternal age. Compared to fathers aged 20-29 years, fathers <20 years (OR 3.15, 95% CI 1.99, 4.98) and 20-24 years (OR 1.39, 95% CI 1.11, 1.73) had increased odds of trisomy 21 offspring, after adjusting for maternal and paternal race/ethnicity and maternal age. Results were consistent after excluding stillbirths, multiples, and trisomy 21 due to translocation or mosaicism. CONCLUSIONS: Maternal age is an important risk factor for trisomy 21 offspring; however, this population-based study shows that that young paternal age is also associated with trisomy 21, after taking into account maternal age and race/ethnicity.

Rare protein-coding variants implicate genes involved in risk of suicide death.

Identification of genetic factors leading to increased risk of suicide death is critical to combat rising suicide rates, however, only a fraction of the genetic variation influencing risk has been accounted for. To address this limitation, we conducted the first comprehensive analysis of rare genetic variation in suicide death leveraging the largest suicide death biobank, the Utah Suicide Genetic Risk Study (USGRS). We conducted a single-variant association analysis of rare (minor allele frequency <1%) putatively functional single-nucleotide polymorphisms (SNPs) present on the Illumina PsychArray genotyping array in 2,672 USGRS suicide deaths of non-Finnish European (NFE) ancestry and 51,583 NFE controls from the Genome Aggregation Database. Secondary analyses used an independent control sample of 21,324 NFE controls from the Psychiatric Genomics Consortium. Five novel, high-impact, rare SNPs were identified with significant associations with suicide death (SNAPC1, rs75418419; TNKS1BP1, rs143883793; ADGRF5, rs149197213; PER1, rs145053802; and ESS2, rs62223875). 119 suicide decedents carried these high-impact SNPs. Both PER1 and SNAPC1 have other supporting gene-level evidence of suicide risk, and psychiatric associations exist for PER1 (bipolar disorder, schizophrenia), and for TNKS1BP1 and ESS2 (schizophrenia). Three of the genes (PER1, TNKS1BP1, and ADGRF5), together with additional genes implicated by genome-wide association studies on suicidal behavior, showed significant enrichment in immune system, homeostatic and signal transduction processes. No specific diagnostic phenotypes were associated with the subset of suicide deaths with the identified rare variants. These findings suggest an important role for rare variants in suicide risk and implicate genes and gene pathways for targeted replication.

Adverse respiratory outcomes among head and neck cancer survivors in the Utah Cancer Survivors Study.

BACKGROUND: The number of head and neck cancer (HNC) survivors has been increasing because of improving survival in the United States. The aim of this study was to evaluate the incidence of respiratory disease diagnoses in HNC survivors in comparison with cancer-free individuals. A second aim was to investigate risk factors for respiratory disease among HNC survivors. METHODS: Patients with HNC diagnosed from 1996 to 2012 were identified in the Utah Cancer Registry (n = 1901). Up to 5 cancer-free individuals from the general population (n = 7796) were matched to each HNC survivor by birth year, sex, birth state, and follow-up time. Electronic medical records and statewide health care facility data were used to identify a disease diagnosis after the cancer diagnosis. Cox proportional hazards models were used to estimate the risks of respiratory diseases. RESULTS: The median follow-up times were 4.5 years for HNC survivors and 7.8 years for the general population cohort. The risks of respiratory infection (hazard ratio [HR], 1.63; 95% confidence interval [CI], 1.40-1.90), chronic obstructive pulmonary diseases and bronchiectasis (HR, 2.65; 95% CI, 2.13-3.29), and aspiration pneumonitis (HR, 6.21; 95% CI, 3.98-9.68) were higher among HNC survivors than the general population cohort more than 5 years after the cancer diagnosis. Age at diagnosis, baseline body mass index, sex, baseline smoking status, treatment modality, primary site, and stage were associated with the risk of adverse respiratory outcomes among HNC survivors. CONCLUSIONS: The risk of adverse respiratory outcomes was much higher among HNC survivors than the general population cohort. Multidisciplinary care is needed to prevent the occurrence of adverse respiratory outcomes among HNC survivors.

Rural-urban disparities in colorectal cancer survival and risk among men in Utah: a statewide population-based study.

Rural areas of the U.S. experience disproportionate colorectal cancer (CRC) death compared to urban areas. The authors aimed to analyze differences in CRC survival between rural and urban Utah men and investigate potential prognostic factors for survival among these men. A cohort of Utah men diagnosed with CRC between 1997 and 2013 was identified from the Utah Cancer Registry. Survival and prognostic factors were analyzed via 5-year CRC survival and Cox proportional hazards models, stratified by rural/urban residence. Among 4,660 men diagnosed with CRC, 15.3% were living in rural Utah. Compared with urban men, rural CRC patients were diagnosed at older ages and in different anatomic subsites; more were overweight, and current smokers. Differences in stage and treatment were not apparent between rural and urban CRC patients. Compared with urban counterparts, rural men experienced a lower CRC survival (Hazard Ratio 0.55, 95% CI 0.53, 0.58 vs. 0.58, 95% CI 0.56, 0.59). Race and cancer treatment influenced CRC survival among men living in both urban and rural areas. Factors of CRC survival varied greatly among urban and rural men in Utah. The influence of social and environmental conditions on health behaviors and outcomes merits further exploration.

Genitourinary disease risks among ovarian cancer survivors in a population-based cohort study.

OBJECTIVE: While genitourinary complications during treatment for ovarian cancer are well-known, long-term adverse outcomes have not been well characterized. The number of ovarian cancer survivors has been increasing. The aim of this study was to investigate long-term adverse genitourinary outcomes in a population-based cohort. METHODS: We identified a cohort of 1270 ovarian cancer survivors diagnosed between 1996 and 2012 from the Utah Cancer Registry, and 5286 cancer-free women were matched on birth year and state from the Utah Population Database. Genitourinary disease diagnoses were identified through ICD-9 codes from electronic medical records and statewide healthcare facilities data. Cox proportional hazards models were used to estimate hazard ratios (HR) for genitourinary outcomes at 1 to <5 years and 5+ years after ovarian cancer diagnosis. RESULTS: Ovarian cancer survivors had increased risks for urinary system disorders (HR: 2.53, 95% CI: 2.12-3.01) and genital organ disorders (HR: 1.88, 95% CI: 1.57-2.27) between 1 and <5 years after cancer diagnosis compared to the general population cohort. Increased risks were observed for acute renal failure, chronic kidney disease, calculus of kidney, hydronephrosis, pelvic peritoneal adhesions, and pelvic organ inflammatory conditions. Increased risks of several of these diseases were observed 5+ years after cancer diagnosis. CONCLUSIONS: Ovarian cancer survivors experience increased risks of various genitourinary diseases compared to women in the general population in the long-term. Understanding the multimorbidity trajectory among ovarian cancer survivors is important to improve clinical care after cancer treatment is completed.

Long-term diabetes risk among endometrial cancer survivors in a population-based cohort study.

OBJECTIVE: The majority of endometrial cancer patients are overweight or obese at cancer diagnosis. Obesity is a shared risk factor for both endometrial cancer and diabetes, but it is unknown whether endometrial cancer patients have increased diabetes risks. The aim of our study was to investigate diabetes risk among endometrial cancer patients. METHODS: Endometrial cancer patients diagnosed between 1997 and 2012 in Utah (n = 2,314) were identified. Women from the general population (n = 8,583) were matched to the cancer patients on birth year and birth state. Diabetes diagnoses were identified from electronic medical records and statewide healthcare facility databases. Cox proportional hazards models were used to estimate hazard ratios for diabetes after cancer diagnosis. RESULTS: Endometrial cancer survivors had a significantly higher risk of type II diabetes when compared to women from the general population in the first year after cancer diagnosis (HR = 5.22, 95% CI = 4.05, 6.71), >1-5 years after cancer diagnosis (HR = 1.67, 95% CI = 1.31, 2.12), and >5 years after cancer diagnosis (HR = 1.65, 95% CI = 1.29, 2.11). Endometrial cancer patients who were obese at cancer diagnosis had a three-fold increase in type II diabetes risk (HR = 2.99, 95%CI = 2.59, 3.45). Although endometrial cancer patients diagnosed at distant stage had a higher risk of diabetes, cancer treatment did not appear to contribute to any diabetes risks. CONCLUSIONS: In conclusion, endometrial cancer survivors had a higher risk of diabetes than women in the general population. These results suggest that long term monitoring for diabetes is indicated for endometrial cancer survivors.