Thyroid stimulating hormone (TSH) is critical for normal development and metabolism. To better understand the genetic contribution to TSH levels, we conduct a GWAS meta-analysis at 22.4 million ...genetic markers in up to 119,715 individuals and identify 74 genome-wide significant loci for TSH, of which 28 are previously unreported. Functional experiments show that the thyroglobulin protein-altering variants P118L and G67S impact thyroglobulin secretion. Phenome-wide association analysis in the UK Biobank demonstrates the pleiotropic effects of TSH-associated variants and a polygenic score for higher TSH levels is associated with a reduced risk of thyroid cancer in the UK Biobank and three other independent studies. Two-sample Mendelian randomization using TSH index variants as instrumental variables suggests a protective effect of higher TSH levels (indicating lower thyroid function) on risk of thyroid cancer and goiter. Our findings highlight the pleiotropic effects of TSH-associated variants on thyroid function and growth of malignant and benign thyroid tumors.
Biobanks linked to electronic health records provide rich resources for health‐related research. With improvements in administrative and informatics infrastructure, the availability and utility of ...data from biobanks have dramatically increased. In this paper, we first aim to characterize the current landscape of available biobanks and to describe specific biobanks, including their place of origin, size, and data types. The development and accessibility of large‐scale biorepositories provide the opportunity to accelerate agnostic searches, expedite discoveries, and conduct hypothesis‐generating studies of disease‐treatment, disease‐exposure, and disease‐gene associations. Rather than designing and implementing a single study focused on a few targeted hypotheses, researchers can potentially use biobanks' existing resources to answer an expanded selection of exploratory questions as quickly as they can analyze them. However, there are many obvious and subtle challenges with the design and analysis of biobank‐based studies. Our second aim is to discuss statistical issues related to biobank research such as study design, sampling strategy, phenotype identification, and missing data. We focus our discussion on biobanks that are linked to electronic health records. Some of the analytic issues are illustrated using data from the Michigan Genomics Initiative and UK Biobank, two biobanks with two different recruitment mechanisms. We summarize the current body of literature for addressing these challenges and discuss some standing open problems. This work complements and extends recent reviews about biobank‐based research and serves as a resource catalog with analytical and practical guidance for statisticians, epidemiologists, and other medical researchers pursuing research using biobanks.
The possible association of Cytomegalovirus (CMV) with human colorectal adenocarcinomas was first reported in 1978 by Huang and Roche, who detected CMV DNA in 4 of 7 colonic adenocarcinomas by ...membrane complementary Ribonucleic AcidDeoxyribonucleic Acid (RNA-DNA) hybridisation. CMV earns its name from the characteristic cytomegalic appearance of intranuclear inclusions in infected cells, which include endothelial cells, histiocytes, macrophages, and epithelial cells. The most common site of CMV infection in the gastrointestinal tract is the colon (55%), followed by the sigmoid colon and rectum (35%) and the gastric antrum (25%). Here, a middle-aged female presenting with pain in the lower abdomen, which was insidious in onset and gradually progressive. Ultrasonography revealed a large intestine dilated and filled with multiple air-fluid levels, indicating bowel obstruction. Multidetector Computed Tomography (MDCT) showed circumferential wall thickening involving the distal half of the transverse colon and descending colon. The case was subjected to laparotomy. The resected segment of the colon was sent for histopathological evaluation, and microscopic examination showed adenocarcinoma and many mucosal ulcers, which on keen observation revealed viral inclusions. The diagnosis of colon adenocarcinoma, with a pathological staging of pT2N0Mx with CMV infection, was rendered. CMV infection was confirmed by immunohistochemistry. The patient was on post-surgery chemotherapy and receiving ganciclovir. On follow-up, the patient was recovering fine. Histopathology examination and IHC remain the gold standard in diagnosing CMV, and the concurrent occurrence of colitis and carcinoma should be kept in mind to assist in proper management.
Nightmares are vivid, extended, and emotionally negative or negative dreams that awaken the dreamer. While sporadic nightmares and bad dreams are common and generally harmless, frequent nightmares ...often reflect underlying pathologies of emotional regulation. Indeed, insomnia, depression, anxiety, or alcohol use have been associated with nightmares in epidemiological and clinical studies. However, the connection between nightmares and their comorbidities are poorly understood. Our goal was to examine the genetic risk factors for nightmares and estimate correlation or causality between nightmares and comorbidities. We performed a genome-wide association study (GWAS) in 45,255 individuals using a questionnaire-based assessment on the frequency of nightmares during the past month and genome-wide genotyping data. While the GWAS did not reveal individual risk variants, heritability was estimated at 5%. In addition, the genetic correlation analysis showed a robust correlation (rg > 0.4) of nightmares with anxiety (rg = 0.671, p = 7.507e-06), depressive (rg = 0.562, p = 1.282e-07) and posttraumatic stress disorders (rg = 0.4083, p = 0.0152), and personality trait neuroticism (rg = 0.667, p = 4.516e-07). Furthermore, Mendelian randomization suggested causality from insomnia to nightmares (beta = 0.027, p = 0.0002). Our findings suggest that nightmares share genetic background with psychiatric traits and that insomnia may increase an individual's liability to experience frequent nightmares. Given the significant correlations with psychiatric and psychological traits, it is essential to grow awareness of how nightmares affect health and disease and systematically collect information about nightmares, especially from clinical samples and larger cohorts.
Meta-analysis of genetic association studies increases sample size and the power for mapping complex traits. Existing methods are mostly developed for datasets without missing values, i.e. the ...summary association statistics are measured for all variants in contributing studies. In practice, genotype imputation is not always effective. This may be the case when targeted genotyping/sequencing assays are used or when the un-typed genetic variant is rare. Therefore, contributed summary statistics often contain missing values. Existing methods for imputing missing summary association statistics and using imputed values in meta-analysis, approximate conditional analysis, or simple strategies such as complete case analysis all have theoretical limitations. Applying these approaches can bias genetic effect estimates and lead to seriously inflated type-I or type-II errors in conditional analysis, which is a critical tool for identifying independently associated variants. To address this challenge and complement imputation methods, we developed a method to combine summary statistics across participating studies and consistently estimate joint effects, even when the contributed summary statistics contain large amounts of missing values. Based on this estimator, we proposed a score statistic called PCBS (partial correlation based score statistic) for conditional analysis of single-variant and gene-level associations. Through extensive analysis of simulated and real data, we showed that the new method produces well-calibrated type-I errors and is substantially more powerful than existing approaches. We applied the proposed approach to one of the largest meta-analyses to date for the cigarettes-per-day phenotype. Using the new method, we identified multiple novel independently associated variants at known loci for tobacco use, which were otherwise missed by alternative methods. Together, the phenotypic variance explained by these variants was 1.1%, improving that of previously reported associations by 71%. These findings illustrate the extent of locus allelic heterogeneity and can help pinpoint causal variants.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Biobanks of linked clinical patient histories and biological samples are an efficient strategy to generate large cohorts for modern genetics research. Biobank recruitment varies by factors such as ...geographic catchment and sampling strategy, which affect biobank demographics and research utility. Here, we describe the Michigan Genomics Initiative (MGI), a single-health-system biobank currently consisting of >91,000 participants recruited primarily during surgical encounters at Michigan Medicine. The surgical enrollment results in a biobank enriched for many diseases and ideally suited for a disease genetics cohort. Compared with the much larger population-based UK Biobank, MGI has higher prevalence for nearly all diagnosis-code-based phenotypes and larger absolute case counts for many phenotypes. Genome-wide association study (GWAS) results replicate known findings, thereby validating the genetic and clinical data. Our results illustrate that opportunistic biobank sampling within single health systems provides a unique and complementary resource for exploring the genetics of complex diseases.
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•The Michigan Genomics Initiative (MGI) is a biobank of Michigan Medicine patients•MGI participants are primarily recruited during surgical procedures•The surgical enrollment enriches clinical outcomes relative to population-based biobanks•Summary statistics for GWASs performed in MGI are available to interested researchers
Zawistowski et al. present the Michigan Genomics Initiative, a biobank of linked genotype and clinical data among patients at Michigan Medicine. This health-system-based biobank opportunistically recruits primarily surgical patients, yielding higher case counts than much larger population-based biobanks, enabling genetic research for a wide range of traits.
The recent integration of genomic data with electronic health records has enabled large scale genomic studies on a variety of perioperative complications, yet genome-wide association studies on acute ...kidney injury have been limited in size or confounded by composite outcomes. Genome-wide association studies can be leveraged to create a polygenic risk score which can then be integrated with traditional clinical risk factors to better predict postoperative complications, like acute kidney injury.
Using integrated genetic data from two academic biorepositories, we conduct a genome-wide association study on cardiac surgery-associated acute kidney injury. Next, we develop a polygenic risk score and test the predictive utility within regressions controlling for age, gender, principal components, preoperative serum creatinine, and a range of patient, clinical, and procedural risk factors. Finally, we estimate additive variant heritability using genetic mixed models.
Among 1,014 qualifying procedures at Vanderbilt University Medical Center and 478 at Michigan Medicine, 348 (34.3%) and 121 (25.3%) developed AKI, respectively. No variants exceeded genome-wide significance (
< 5 × 10
) threshold, however, six previously unreported variants exceeded the suggestive threshold (
< 1 × 10
). Notable variants detected include: 1) rs74637005, located in the exonic region of
and 2) rs17438465, located between
and
. We failed to replicate variants from prior unbiased studies of post-surgical acute kidney injury. Polygenic risk was not significantly associated with post-surgical acute kidney injury in any of the models, however, case duration (aOR = 1.002, 95% CI 1.000-1.003,
= 0.013), diabetes mellitus (aOR = 2.025, 95% CI 1.320-3.103,
= 0.001), and valvular disease (aOR = 0.558, 95% CI 0.372-0.835,
= 0.005) were significant in the full model.
Polygenic risk score was not significantly associated with cardiac surgery-associated acute kidney injury and acute kidney injury may have a low heritability in this population. These results suggest that susceptibility is only minimally influenced by baseline genetic predisposition and that clinical risk factors, some of which are modifiable, may play a more influential role in predicting this complication. The overall impact of genetics in overall risk for cardiac surgery-associated acute kidney injury may be small compared to clinical risk factors.
Gut dysmotility is associated with constipation, diarrhea, and functional gastrointestinal disorders like irritable bowel syndrome (IBS), although its molecular underpinnings are poorly ...characterized. We studied stool frequency (defined by the number of bowel movements per day, based on questionnaire data) as a proxy for gut motility in a GWAS meta-analysis including 167,875 individuals from UK Biobank and four smaller population-based cohorts. We identify 14 loci associated with stool frequency (p ≤ 5.0 × 10−8). Gene set and pathway analyses detected enrichment for genes involved in neurotransmitter/neuropeptide signaling and preferentially expressed in enteric motor neurons controlling peristalsis. PheWAS identified pleiotropic associations with dysmotility syndromes and the response to their pharmacological treatment. The genetic architecture of stool frequency correlates with that of IBS, and UK Biobank participants from the top 1% of stool frequency polygenic score distribution were associated with 5× higher risk of IBS with diarrhea. These findings pave the way for the identification of actionable pathological mechanisms in IBS and the dysmotility syndromes.
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Genetics of gut motility via data on stool frequency in 167,875 individualsGWAS identifies 14 loci associated with stool frequencyCandidate genes enriched in neurotransmitter signaling and enteric motor neuronsPolygenic scores predict increased risk of irritable bowel syndrome
Bonfiglio et al. investigate the genetics of human gut motility using genotype and questionnaire data on stool frequency in 167,875 individuals from the UK Biobank and four other cohorts. They identify 14 loci associated with stool frequency as well as candidate genes enriched in neurotransmitter signaling and preferentially expressed in enteric neurons controlling peristalsis. The genetic architecture of stool frequency correlates with that of irritable bowel syndrome (IBS), and stool frequency polygenic scores were predictive of IBS risk.
Prior studies support a genetic basis for postoperative acute kidney injury (AKI). We conducted a genome-wide association study (GWAS), assessed the clinical utility of a polygenic risk score (PRS), ...and estimated the heritable component of AKI in patients who underwent noncardiac surgery.
We performed a retrospective large-scale genome-wide association study followed by a meta-analysis of patients who underwent noncardiac surgery at the Vanderbilt University Medical Center ("Vanderbilt" cohort) or Michigan Medicine, the academic medical center of the University of Michigan ("Michigan" cohort). In the Vanderbilt cohort, the relationship between polygenic risk score for estimated glomerular filtration rate and postoperative AKI was also tested to explore the predictive power of aggregating multiple common genetic variants associated with AKI risk. Similarly, in the Vanderbilt cohort genome-wide complex trait analysis was used to estimate the heritable component of AKI due to common genetic variants.
The study population included 8248 adults in the Vanderbilt cohort (mean SD 58.05 15.23 years, 50.2% men) and 5998 adults in Michigan cohort (56.24 14.76 years, 49% men). Incident postoperative AKI events occurred in 959 patients (11.6%) and in 277 patients (4.6%), respectively. No loci met genome-wide significance in the GWAS and meta-analysis. PRS for estimated glomerular filtration rate explained a very small percentage of variance in rates of postoperative AKI and was not significantly associated with AKI (odds ratio 1.050 per 1 SD increase in polygenic risk score 95% CI, 0.971-1.134). The estimated heritability among common variants for AKI was 4.5% (SE = 4.5%) suggesting low heritability.
The findings of this study indicate that common genetic variation minimally contributes to postoperative AKI after noncardiac surgery, and likely has little clinical utility for identifying high-risk patients.
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