Publications by authors named "Cristen J Willer"

135 Publications

Discovery and prioritization of variants and genes for kidney function in >1.2 million individuals.

Nat Commun 2021 07 16;12(1):4350. Epub 2021 Jul 16.

Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany.

Genes underneath signals from genome-wide association studies (GWAS) for kidney function are promising targets for functional studies, but prioritizing variants and genes is challenging. By GWAS meta-analysis for creatinine-based estimated glomerular filtration rate (eGFR) from the Chronic Kidney Disease Genetics Consortium and UK Biobank (n = 1,201,909), we expand the number of eGFRcrea loci (424 loci, 201 novel; 9.8% eGFRcrea variance explained by 634 independent signal variants). Our increased sample size in fine-mapping (n = 1,004,040, European) more than doubles the number of signals with resolved fine-mapping (99% credible sets down to 1 variant for 44 signals, ≤5 variants for 138 signals). Cystatin-based eGFR and/or blood urea nitrogen association support 348 loci (n = 460,826 and 852,678, respectively). Our customizable tool for Gene PrioritiSation reveals 23 compelling genes including mechanistic insights and enables navigation through genes and variants likely relevant for kidney function in human to help select targets for experimental follow-up.
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http://dx.doi.org/10.1038/s41467-021-24491-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285412PMC
July 2021

Regulatory variants in TCF7L2 are associated with thoracic aortic aneurysm.

Am J Hum Genet 2021 09 14;108(9):1578-1589. Epub 2021 Jul 14.

K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim 7030, Norway.

Thoracic aortic aneurysm (TAA) is characterized by dilation of the aortic root or ascending/descending aorta. TAA is a heritable disease that can be potentially life threatening. While 10%-20% of TAA cases are caused by rare, pathogenic variants in single genes, the origin of the majority of TAA cases remains unknown. A previous study implicated common variants in FBN1 with TAA disease risk. Here, we report a genome-wide scan of 1,351 TAA-affected individuals and 18,295 control individuals from the Cardiovascular Health Improvement Project and Michigan Genomics Initiative at the University of Michigan. We identified a genome-wide significant association with TAA for variants within the third intron of TCF7L2 following replication with meta-analysis of four additional independent cohorts. Common variants in this locus are the strongest known genetic risk factor for type 2 diabetes. Although evidence indicates the presence of different causal variants for TAA and type 2 diabetes at this locus, we observed an opposite direction of effect. The genetic association for TAA colocalizes with an aortic eQTL of TCF7L2, suggesting a functional relationship. These analyses predict an association of higher expression of TCF7L2 with TAA disease risk. In vitro, we show that upregulation of TCF7L2 is associated with BCL2 repression promoting vascular smooth muscle cell apoptosis, a key driver of TAA disease.
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http://dx.doi.org/10.1016/j.ajhg.2021.06.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8456156PMC
September 2021

Identification of ACE2 modifiers by CRISPR screening.

bioRxiv 2021 Jun 10. Epub 2021 Jun 10.

SARS-CoV-2 infection is initiated by binding of the viral spike protein to its receptor, ACE2, on the surface of host cells. ACE2 expression is heterogeneous both and in immortalized cell lines, but the molecular pathways that govern ACE2 expression remain unclear. We now report high-throughput CRISPR screens for functional modifiers of ACE2 surface abundance. We identified 35 genes whose disruption was associated with a change in the surface abundance of ACE2 in HuH7 cells. Enriched among these ACE2 regulators were established transcription factors, epigenetic regulators, and functional networks. We further characterized individual cell lines with disruption of , or and found these genes to regulate ACE2 at the mRNA level and to influence cellular susceptibility to SARS-CoV-2 infection. Collectively, our findings clarify the host factors involved in SARS-CoV-2 entry and suggest potential targets for therapeutic development.
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http://dx.doi.org/10.1101/2021.06.10.447768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202422PMC
June 2021

Cardiorespiratory Fitness After Open Repair for Acute Type A Aortic Dissection - A Prospective Study.

Semin Thorac Cardiovasc Surg 2021 Jun 6. Epub 2021 Jun 6.

Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Michigan Medicine, Ann Arbor, Michigan. Electronic address:

Cardiorespiratory fitness (as measured by peak oxygen consumption [VO]) is an independent predictor of cardiovascular disease and all-cause mortality. Limited data exist on VO following repair for an acute type A aortic dissection (ATAAD) or proximal thoracic aortic aneurysm (pTAA). This study prospectively evaluated VO, functional capacity, and health-related quality of life (HR-QOL) following open repair. Participants with a history of an ATAAD (n = 21) or pTAA (n = 43) performed cardiopulmonary exercise testing (CPX), 6-minute walk testing, and HR-QOL at 3 (early) and 15 (late) months following open repair. The median age at time of surgery was 55-years-old and 60-years-old in the ATAAD and pTAA groups, respectively. Body mass index significantly increased between early and late timepoints for both ATAAD (p = 0.0245, 56% obese) and pTAA groups (p = 0.0045, 54% obese). VO modestly increased by 0.8 mLO2·kg-1·min-1 within the ATAAD group (p = 0.2312) while VO significantly increased by 2.2 mLO2·kg-1·min-1 within the pTAA group (p = 0.0003). Anxiety significantly decreased in the ATAAD group whereas functional capacity and HR-QOL metrics (social roles and activities, physical function) significantly improved in the pTAA group (p values < 0.05). There were no serious adverse events during CPX. Cardiorespiratory fitness among the ATAAD group remained 36% below predicted normative values >1 year after repair. CPX should be considered post-operatively to evaluate exercise tolerance and blood pressure response to determine whether mild-to-moderate aerobic exercise should be recommended to reduce future risk of morbidity and mortality.
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http://dx.doi.org/10.1053/j.semtcvs.2021.05.017DOI Listing
June 2021

Development and Validation of a Polygenic Risk Score for Stroke in the Chinese Population.

Neurology 2021 08 24;97(6):e619-e628. Epub 2021 May 24.

From the Key Laboratory of Cardiovascular Epidemiology and Department of Epidemiology (Xiangfeng Lu, X.N., Fangchao Liu, Z.L., K.H., L.W., J.L., J.C., S.C., H.L., Xigui Wu, Y.L., J.H., D.G.), State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing; Department of Epidemiology and Biostatistics (C.S., Z.H., H.S.), Center for Global Health, School of Public Health, Nanjing Medical University; Department of Biostatistics and Epidemiology (D.H.), School of Public Health, Shenzhen University Health Science Center, Guangdong; Cardio-Cerebrovascular Control and Research Center (Y.Z., Fanghong Lu), Institute of Basic Medicine, Shandong First Medical University (Shandong Academy of Medical Sciences), Jinan; Tianjin Key Laboratory of Environment, Nutrition and Public Health (X.Y.), Department of Occupational and Environmental Health, School of Public Health, Tianjin Medical University, Tianjin; Division of Epidemiology (Xiaoqing Liu), Guangdong Provincial People's Hospital and Cardiovascular Institute, Guangzhou; Department of Neurology (W.T., Z.R.), Affiliated Yixing People's Hospital of Jiangsu University, People's Hospital of Yixing City, Yixing; Department of Cardiology (L.Y.), Fujian Provincial Hospital, Fuzhou; Center for Chronic and Noncommunicable Disease Control and Prevention (Xianping Wu), Sichuan Center for Disease Control and Prevention, Chengdu; Center for Genetic Epidemiology and Genomics (H.Z.), School of Public Health and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Medical College of Soochow University, Suzhou; Research Unit of Prospective Cohort of Cardiovascular Diseases and Cancer (H.S.), Chinese Academy of Medical Sciences (2019RU038); and Department of Internal Medicine, Division of Cardiovascular Medicine (C.J.W.), and Department of Human Genetics (C.J.W.), University of Michigan, Ann Arbor.

Objective: To construct a polygenic risk score (PRS) for stroke and evaluate its utility in risk stratification and primary prevention for stroke.

Methods: Using a meta-analytic approach and large genome-wide association results for stroke and stroke-related traits in East Asians, we generated a combined PRS (metaPRS) by incorporating 534 genetic variants in a training set of 2,872 patients with stroke and 2,494 controls. We then validated its association with incident stroke using Cox regression models in large Chinese population-based prospective cohorts comprising 41,006 individuals.

Results: During a total of 367,750 person-years (mean follow-up 9.0 years), 1,227 participants developed stroke before age 80 years. Individuals with high polygenic risk had an about 2-fold higher risk of incident stroke compared with those with low polygenic risk (hazard ratio [HR] 1.99, 95% confidence interval [CI] 1.66-2.38), with the lifetime risk of stroke being 25.2% (95% CI 22.5%-27.7%) and 13.6% (95% CI 11.6%-15.5%), respectively. Individuals with both high polygenic risk and family history displayed lifetime risk as high as 41.1% (95% CI 31.4%-49.5%). Individuals with high polygenic risk achieved greater benefits in terms of absolute risk reductions from adherence to ideal fasting blood glucose and total cholesterol than those with low polygenic risk. Maintaining favorable cardiovascular health (CVH) profile could substantially mitigate the increased risk conferred by high polygenic risk to the level of low polygenic risk (from 34.6% to 13.2%).

Conclusions: Our metaPRS has great potential for risk stratification of stroke and identification of individuals who may benefit more from maintaining ideal CVH.

Classification Of Evidence: This study provides Class I evidence that metaPRS is predictive of stroke risk.
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http://dx.doi.org/10.1212/WNL.0000000000012263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8424497PMC
August 2021

Genome-wide association study of cardiac troponin I in the general population.

Hum Mol Genet 2021 Oct;30(21):2027-2039

Division of Research and Innovation, Akershus University Hospital, 1478 Lørenskog, Norway.

Circulating cardiac troponin proteins are associated with structural heart disease and predict incident cardiovascular disease in the general population. However, the genetic contribution to cardiac troponin I (cTnI) concentrations and its causal effect on cardiovascular phenotypes are unclear. We combine data from two large population-based studies, the Trøndelag Health Study and the Generation Scotland Scottish Family Health Study, and perform a genome-wide association study of high-sensitivity cTnI concentrations with 48 115 individuals. We further use two-sample Mendelian randomization to investigate the causal effects of circulating cTnI on acute myocardial infarction (AMI) and heart failure (HF). We identified 12 genetic loci (8 novel) associated with cTnI concentrations. Associated protein-altering variants highlighted putative functional genes: CAND2, HABP2, ANO5, APOH, FHOD3, TNFAIP2, KLKB1 and LMAN1. Phenome-wide association tests in 1688 phecodes and 83 continuous traits in UK Biobank showed associations between a genetic risk score for cTnI and cardiac arrhythmias, metabolic and anthropometric measures. Using two-sample Mendelian randomization, we confirmed the non-causal role of cTnI in AMI (5948 cases, 355 246 controls). We found indications for a causal role of cTnI in HF (47 309 cases and 930 014 controls), but this was not supported by secondary analyses using left ventricular mass as outcome (18 257 individuals). Our findings clarify the biology underlying the heritable contribution to circulating cTnI and support cTnI as a non-causal biomarker for AMI in the general population. Using genetically informed methods for causal inference helps inform the role and value of measuring cTnI in the general population.
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http://dx.doi.org/10.1093/hmg/ddab124DOI Listing
October 2021

An Asian-specific MPL genetic variant alters JAK-STAT signaling and influences platelet count in the population.

Hum Mol Genet 2021 May;30(9):836-842

Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.

Genomic discovery efforts for hematological traits have been successfully conducted through genome-wide association study on samples of predominantly European ancestry. We sought to conduct unbiased genetic discovery for coding variants that influence hematological traits in a Han Chinese population. A total of 5257 Han Chinese subjects from Beijing, China were included in the discovery cohort and analyzed by an Illumina ExomeChip array. Replication analyses were conducted in 3827 independent Chinese subjects. We analyzed 12 hematological traits and identified 22 exome-wide significant single-nucleotide polymorphisms (SNP)-trait associations with 15 independent SNPs. Our study provides replication for two associations previously reported but not replicated. Further, one association was identified and replicated in the current study, of a coding variant in the myeloproliferative leukemia (MPL) gene, c.793C > T, p.Leu265Phe (L265F) with increased platelet count (β = 20.6 109 cells/l, Pmeta-analysis = 2.6 × 10-13). This variant is observed at ~2% population frequency in East Asians, whereas it has not been reported in gnomAD European or African populations. Functional analysis demonstrated that expression of MPL L265F in Ba/F3 cells resulted in enhanced phosphorylation of Stat3 and ERK1/2 as compared with the reference MPL allele, supporting altered activation of the JAK-STAT signal transduction pathway as the mechanism underlying the novel association between MPL L265F and platelet count.
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http://dx.doi.org/10.1093/hmg/ddab062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8161516PMC
May 2021

GWAS Identifies LINC01184/SLC12A2 as a Risk Locus for Skin and Soft Tissue Infections.

J Invest Dermatol 2021 Aug 1;141(8):2083-2086.e8. Epub 2021 Mar 1.

Gemini Center for Sepsis Research, Department of Circulation and Medical Imaging, NTNU Norwegian University of Science and Technology, Trondheim, Norway; Department of Infectious Diseases, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway; Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, NTNU Norwegian University of Science and Technology, Trondheim, Norway.

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http://dx.doi.org/10.1016/j.jid.2021.01.020DOI Listing
August 2021

Translating genetic association of lipid levels for biological and clinical application.

Cardiovasc Drugs Ther 2021 06 19;35(3):617-626. Epub 2021 Feb 19.

Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Michigan Medicine, Ann Arbor, MI, USA.

Purpose Of Review: This review focuses on the foundational evidence from the last two decades of lipid genetics research and describes the current status of data-driven approaches for transethnic GWAS, fine-mapping, transcriptome informed fine-mapping, and disease prediction.

Recent Findings: Current lipid genetics research aims to understand the association mechanisms and clinical relevance of lipid loci as well as to capture population specific associations found in global ancestries. Recent genome-wide trans-ethnic association meta-analyses have identified 118 novel lipid loci reaching genome-wide significance. Gene-based burden tests of whole exome sequencing data have identified three genes-PCSK9, LDLR, and APOB-with significant rare variant burden associated with familial dyslipidemia. Transcriptome-wide association studies discovered five previously unreported lipid-associated loci. Additionally, the predictive power of genome-wide genetic risk scores amalgamating the polygenic determinants of lipid levels can potentially be used to increase the accuracy of coronary artery disease prediction.

Conclusions: Lipids are one of the most successful group of traits in the era of genome-wide genetic discovery for identification of novel loci and plausible drug targets. However, a substantial fraction of lipid trait heritability remains unexplained. Further analysis of diverse ancestries and state of the art methods for association locus refinement could potentially reveal some of this missing heritability and increase the clinical application of the genomic association results.
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http://dx.doi.org/10.1007/s10557-021-07156-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8272953PMC
June 2021

Genetic insight into sick sinus syndrome.

Eur Heart J 2021 05;42(20):1959-1971

deCODE genetics/Amgen, Inc., Sturlugata 8, Reykjavik 101, Iceland.

Aims: The aim of this study was to use human genetics to investigate the pathogenesis of sick sinus syndrome (SSS) and the role of risk factors in its development.

Methods And Results: We performed a genome-wide association study of 6469 SSS cases and 1 000 187 controls from deCODE genetics, the Copenhagen Hospital Biobank, UK Biobank, and the HUNT study. Variants at six loci associated with SSS, a reported missense variant in MYH6, known atrial fibrillation (AF)/electrocardiogram variants at PITX2, ZFHX3, TTN/CCDC141, and SCN10A and a low-frequency (MAF = 1.1-1.8%) missense variant, p.Gly62Cys in KRT8 encoding the intermediate filament protein keratin 8. A full genotypic model best described the p.Gly62Cys association (P = 1.6 × 10-20), with an odds ratio (OR) of 1.44 for heterozygotes and a disproportionally large OR of 13.99 for homozygotes. All the SSS variants increased the risk of pacemaker implantation. Their association with AF varied and p.Gly62Cys was the only variant not associating with any other arrhythmia or cardiovascular disease. We tested 17 exposure phenotypes in polygenic score (PGS) and Mendelian randomization analyses. Only two associated with the risk of SSS in Mendelian randomization, AF, and lower heart rate, suggesting causality. Powerful PGS analyses provided convincing evidence against causal associations for body mass index, cholesterol, triglycerides, and type 2 diabetes (P > 0.05).

Conclusion: We report the associations of variants at six loci with SSS, including a missense variant in KRT8 that confers high risk in homozygotes and points to a mechanism specific to SSS development. Mendelian randomization supports a causal role for AF in the development of SSS.
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http://dx.doi.org/10.1093/eurheartj/ehaa1108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140484PMC
May 2021

Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program.

Nature 2021 02 10;590(7845):290-299. Epub 2021 Feb 10.

The Broad Institute of MIT and Harvard, Cambridge, MA, USA.

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes). In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.
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http://dx.doi.org/10.1038/s41586-021-03205-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875770PMC
February 2021

Exposure and risk factors for COVID-19 and the impact of staying home on Michigan residents.

PLoS One 2021 8;16(2):e0246447. Epub 2021 Feb 8.

Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI, United States of America.

COVID-19 has had a substantial impact on clinical care and lifestyles globally. The State of Michigan reports over 80,000 positive COVID-19 tests between March 1, 2020 and July 29, 2020. We surveyed 8,041 Michigan Medicine biorepository participants in late June 2020. We found that 55% of COVID-19 cases reported no known exposure to family members or to someone outside the house diagnosed with COVID-19. A significantly higher rate of COVID-19 cases were employed as essential workers (45% vs 19%, p = 9x10-12). COVID-19 cases reporting a fever were more likely to require hospitalization (categorized as severe; OR = 4.4 [95% CI: 1.6-12.5, p = 0.005]) whereas respondents reporting rhinorrhea was less likely to require hospitalization (categorized as mild-to-moderate; OR = 0.16 [95% CI: 0.04-0.73, p = 0.018]). African-Americans reported higher rates of being diagnosed with COVID-19 (OR = 4.0 [95% CI: 2.2-7.2, p = 5x10-6]), as well as higher rates of exposure to family or someone outside the household diagnosed with COVID-19, an annual household income < $40,000, living in rental housing, and chronic diseases. During the Executive Order in Michigan, African Americans, women, and the lowest income group reported worsening health behaviors and higher overall concern for the potential detrimental effects of the pandemic. The higher risk of contracting COVID-19 observed among African Americans may be due to the increased rates of working as essential employees, lower socioeconomic status, and exposure to known positive cases. Continued efforts should focus on COVID-19 prevention and mitigation strategies, as well as address the inequality gaps that result in higher risks for both short-term and long-term health outcomes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0246447PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870003PMC
February 2021

Genome-scale CRISPR screening for modifiers of cellular LDL uptake.

PLoS Genet 2021 01 29;17(1):e1009285. Epub 2021 Jan 29.

Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States of America.

Hypercholesterolemia is a causal and modifiable risk factor for atherosclerotic cardiovascular disease. A critical pathway regulating cholesterol homeostasis involves the receptor-mediated endocytosis of low-density lipoproteins into hepatocytes, mediated by the LDL receptor. We applied genome-scale CRISPR screening to query the genetic determinants of cellular LDL uptake in HuH7 cells cultured under either lipoprotein-rich or lipoprotein-starved conditions. Candidate LDL uptake regulators were validated through the synthesis and secondary screening of a customized library of gRNA at greater depth of coverage. This secondary screen yielded significantly improved performance relative to the primary genome-wide screen, with better discrimination of internal positive controls, no identification of negative controls, and improved concordance between screen hits at both the gene and gRNA level. We then applied our customized gRNA library to orthogonal screens that tested for the specificity of each candidate regulator for LDL versus transferrin endocytosis, the presence or absence of genetic epistasis with LDLR deletion, the impact of each perturbation on LDLR expression and trafficking, and the generalizability of LDL uptake modifiers across multiple cell types. These findings identified several previously unrecognized genes with putative roles in LDL uptake and suggest mechanisms for their functional interaction with LDLR.
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http://dx.doi.org/10.1371/journal.pgen.1009285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875399PMC
January 2021

Loss-of-function genomic variants highlight potential therapeutic targets for cardiovascular disease.

Nat Commun 2020 12 18;11(1):6417. Epub 2020 Dec 18.

The Institute for Translational Genomics and Population Sciences, Department of Pediatrics and Los Angeles Biomedical Research Institute, Harbor-UCLA, Torrance, CA, USA.

Pharmaceutical drugs targeting dyslipidemia and cardiovascular disease (CVD) may increase the risk of fatty liver disease and other metabolic disorders. To identify potential novel CVD drug targets without these adverse effects, we perform genome-wide analyses of participants in the HUNT Study in Norway (n = 69,479) to search for protein-altering variants with beneficial impact on quantitative blood traits related to cardiovascular disease, but without detrimental impact on liver function. We identify 76 (11 previously unreported) presumed causal protein-altering variants associated with one or more CVD- or liver-related blood traits. Nine of the variants are predicted to result in loss-of-function of the protein. This includes ZNF529:p.K405X, which is associated with decreased low-density-lipoprotein (LDL) cholesterol (P = 1.3 × 10) without being associated with liver enzymes or non-fasting blood glucose. Silencing of ZNF529 in human hepatoma cells results in upregulation of LDL receptor and increased LDL uptake in the cells. This suggests that inhibition of ZNF529 or its gene product should be prioritized as a novel candidate drug target for treating dyslipidemia and associated CVD.
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http://dx.doi.org/10.1038/s41467-020-20086-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749177PMC
December 2020

Genetic associations with temporal shifts in obesity and severe obesity during the obesity epidemic in Norway: A longitudinal population-based cohort (the HUNT Study).

PLoS Med 2020 12 14;17(12):e1003452. Epub 2020 Dec 14.

Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.

Background: Obesity has tripled worldwide since 1975 as environments are becoming more obesogenic. Our study investigates how changes in population weight and obesity over time are associated with genetic predisposition in the context of an obesogenic environment over 6 decades and examines the robustness of the findings using sibling design.

Methods And Findings: A total of 67,110 individuals aged 13-80 years in the Nord-Trøndelag region of Norway participated with repeated standardized body mass index (BMI) measurements from 1966 to 2019 and were genotyped in a longitudinal population-based health study, the Trøndelag Health Study (the HUNT Study). Genotyping required survival to and participation in the HUNT Study in the 1990s or 2000s. Linear mixed models with observations nested within individuals were used to model the association between a genome-wide polygenic score (GPS) for BMI and BMI, while generalized estimating equations were used for obesity (BMI ≥ 30 kg/m2) and severe obesity (BMI ≥ 35 kg/m2). The increase in the average BMI and prevalence of obesity was steeper among the genetically predisposed. Among 35-year-old men, the prevalence of obesity for the least predisposed tenth increased from 0.9% (95% confidence interval [CI] 0.6% to 1.2%) to 6.5% (95% CI 5.0% to 8.0%), while the most predisposed tenth increased from 14.2% (95% CI 12.6% to 15.7%) to 39.6% (95% CI 36.1% to 43.0%). Equivalently for women of the same age, the prevalence of obesity for the least predisposed tenth increased from 1.1% (95% CI 0.7% to1.5%) to 7.6% (95% CI 6.0% to 9.2%), while the most predisposed tenth increased from 15.4% (95% CI 13.7% to 17.2%) to 42.0% (95% CI 38.7% to 45.4%). Thus, for 35-year-old men and women, respectively, the absolute change in the prevalence of obesity from 1966 to 2019 was 19.8 percentage points (95% CI 16.2 to 23.5, p < 0.0001) and 20.0 percentage points (95% CI 16.4 to 23.7, p < 0.0001) greater for the most predisposed tenth compared with the least predisposed tenth, defined using the GPS for BMI. The corresponding absolute changes in the prevalence of severe obesity for men and women, respectively, were 8.5 percentage points (95% CI 6.3 to 10.7, p < 0.0001) and 12.6 percentage points (95% CI 9.6 to 15.6, p < 0.0001) greater for the most predisposed tenth. The greater increase in BMI in genetically predisposed individuals over time was apparent after adjustment for family-level confounding using a sibling design. Key limitations include a slightly lower survival to date of genetic testing for the older cohorts and that we apply a contemporary genetic score to past time periods. Future research should validate our findings using a polygenic risk score constructed from historical data.

Conclusions: In the context of increasingly obesogenic changes in our environment over 6 decades, our findings reveal a growing inequality in the risk for obesity and severe obesity across GPS tenths. Our results suggest that while obesity is a partially heritable trait, it is still modifiable by environmental factors. While it may be possible to identify those most susceptible to environmental change, who thus have the most to gain from preventive measures, efforts to reverse the obesogenic environment will benefit the whole population and help resolve the obesity epidemic.
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http://dx.doi.org/10.1371/journal.pmed.1003452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735641PMC
December 2020

Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals.

Nat Genet 2020 12 23;52(12):1314-1332. Epub 2020 Nov 23.

Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.

Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.
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http://dx.doi.org/10.1038/s41588-020-00713-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610439PMC
December 2020

Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors.

Nat Genet 2020 12 16;52(12):1303-1313. Epub 2020 Nov 16.

Department of Research, Innovation and Education, Division of Clinical Neuroscience, Oslo University Hospital, Oslo, Norway.

Rupture of an intracranial aneurysm leads to subarachnoid hemorrhage, a severe type of stroke. To discover new risk loci and the genetic architecture of intracranial aneurysms, we performed a cross-ancestry, genome-wide association study in 10,754 cases and 306,882 controls of European and East Asian ancestry. We discovered 17 risk loci, 11 of which are new. We reveal a polygenic architecture and explain over half of the disease heritability. We show a high genetic correlation between ruptured and unruptured intracranial aneurysms. We also find a suggestive role for endothelial cells by using gene mapping and heritability enrichment. Drug-target enrichment shows pleiotropy between intracranial aneurysms and antiepileptic and sex hormone drugs, providing insights into intracranial aneurysm pathophysiology. Finally, genetic risks for smoking and high blood pressure, the two main clinical risk factors, play important roles in intracranial aneurysm risk, and drive most of the genetic correlation between intracranial aneurysms and other cerebrovascular traits.
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http://dx.doi.org/10.1038/s41588-020-00725-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116530PMC
December 2020

MEPE loss-of-function variant associates with decreased bone mineral density and increased fracture risk.

Nat Commun 2020 10 23;11(1):4093. Epub 2020 Oct 23.

Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, 1500 E. Medical Center Dr., Ann Arbor, MI, 48109, USA.

A major challenge in genetic association studies is that most associated variants fall in the non-coding part of the human genome. We searched for variants associated with bone mineral density (BMD) after enriching the discovery cohort for loss-of-function (LoF) mutations by sequencing a subset of the Nord-Trøndelag Health Study, followed by imputation in the remaining sample (N = 19,705), and identified ten known BMD loci. However, one previously unreported variant, LoF mutation in MEPE, p.(Lys70IlefsTer26, minor allele frequency [MAF] = 0.8%), was associated with decreased ultradistal forearm BMD (P-value = 2.1 × 10), and increased osteoporosis (P-value = 4.2 × 10) and fracture risk (P-value = 1.6 × 10). The MEPE LoF association with BMD and fractures was further evaluated in 279,435 UK (MAF = 0.05%, heel bone estimated BMD P-value = 1.2 × 10, any fracture P-value = 0.05) and 375,984 Icelandic samples (MAF = 0.03%, arm BMD P-value = 0.12, forearm fracture P-value = 0.005). Screening for the MEPE LoF mutations before adulthood could potentially prevent osteoporosis and fractures due to the lifelong effect on BMD observed in the study. A key implication for precision medicine is that high-impact functional variants missing from the publicly available cosmopolitan panels could be clinically more relevant than polygenic risk scores.
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http://dx.doi.org/10.1038/s41467-020-17315-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585430PMC
October 2020

Exome sequencing and characterization of 49,960 individuals in the UK Biobank.

Nature 2020 10 21;586(7831):749-756. Epub 2020 Oct 21.

University of Michigan, Ann Arbor, MI, USA.

The UK Biobank is a prospective study of 502,543 individuals, combining extensive phenotypic and genotypic data with streamlined access for researchers around the world. Here we describe the release of exome-sequence data for the first 49,960 study participants, revealing approximately 4 million coding variants (of which around 98.6% have a frequency of less than 1%). The data include 198,269 autosomal predicted loss-of-function (LOF) variants, a more than 14-fold increase compared to the imputed sequence. Nearly all genes (more than 97%) had at least one carrier with a LOF variant, and most genes (more than 69%) had at least ten carriers with a LOF variant. We illustrate the power of characterizing LOF variants in this population through association analyses across 1,730 phenotypes. In addition to replicating established associations, we found novel LOF variants with large effects on disease traits, including PIEZO1 on varicose veins, COL6A1 on corneal resistance, MEPE on bone density, and IQGAP2 and GMPR on blood cell traits. We further demonstrate the value of exome sequencing by surveying the prevalence of pathogenic variants of clinical importance, and show that 2% of this population has a medically actionable variant. Furthermore, we characterize the penetrance of cancer in carriers of pathogenic BRCA1 and BRCA2 variants. Exome sequences from the first 49,960 participants highlight the promise of genome sequencing in large population-based studies and are now accessible to the scientific community.
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http://dx.doi.org/10.1038/s41586-020-2853-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759458PMC
October 2020

Genetic mutations associated with susceptibility to perioperative complications in a longitudinal biorepository with integrated genomic and electronic health records.

Br J Anaesth 2020 12 3;125(6):986-994. Epub 2020 Sep 3.

Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Background: Existing genetic information can be leveraged to identify patients with susceptibilities to conditions that might impact their perioperative care, but clinicians generally have limited exposure and are not trained to contextualise this information. We identified patients with genetic susceptibilities to anaesthetic complications using a perioperative biorepository and characterised the concordance with existing diagnoses.

Methods: Adult patients undergoing surgery within Michigan Medicine from 2012 to 2017 were consented for genotyping. Genotypes were integrated with the electronic health record (EHR). We retrospectively characterised frequencies of variants associated with butyrylcholinesterase deficiency, factor V Leiden, and malignant hyperthermia, three pharmacogenetic factors with perioperative implications. We calculated the percentage homozygous and heterozygous for each that had been diagnosed previously and searched for EHR findings consistent with a predisposition.

Results: Analysis of genetic data revealed that 25 out of 40 769 (0.1%) patients were homozygous and 1918 (4.7%) were heterozygous for mutations associated with butyrylcholinesterase deficiency. Of the homozygous individuals, 14 (56%) carried a pre-existing diagnosis. For factor V Leiden, 29 (0.1%) were homozygous and 2153 (5.3%) heterozygous. Of the homozygous individuals, three (10%) were diagnosed by EHR-derived phenotype and six (21%) by clinician review. Malignant hyperthermia was assessed in a subset of patients. We detected two patients with associated mutations. Neither carried clinical diagnoses.

Conclusions: We identified patients with genetic susceptibility to perioperative complications using an open source script designed for clinician use. We validated this application in a retrospective analysis for three conditions with well-characterised inheritance, and showed that not all genetic susceptibilities were documented in the EHR.
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http://dx.doi.org/10.1016/j.bja.2020.08.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7729841PMC
December 2020

Dynamic incorporation of multiple in silico functional annotations empowers rare variant association analysis of large whole-genome sequencing studies at scale.

Nat Genet 2020 09 24;52(9):969-983. Epub 2020 Aug 24.

Department of Data Sciences, Dana-Farber Cancer Institute and Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Large-scale whole-genome sequencing studies have enabled the analysis of rare variants (RVs) associated with complex phenotypes. Commonly used RV association tests have limited scope to leverage variant functions. We propose STAAR (variant-set test for association using annotation information), a scalable and powerful RV association test method that effectively incorporates both variant categories and multiple complementary annotations using a dynamic weighting scheme. For the latter, we introduce 'annotation principal components', multidimensional summaries of in silico variant annotations. STAAR accounts for population structure and relatedness and is scalable for analyzing very large cohort and biobank whole-genome sequencing studies of continuous and dichotomous traits. We applied STAAR to identify RVs associated with four lipid traits in 12,316 discovery and 17,822 replication samples from the Trans-Omics for Precision Medicine Program. We discovered and replicated new RV associations, including disruptive missense RVs of NPC1L1 and an intergenic region near APOC1P1 associated with low-density lipoprotein cholesterol.
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http://dx.doi.org/10.1038/s41588-020-0676-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483769PMC
September 2020

Complex and Potentially Harmful Medication Patterns in Heart Failure with Preserved Ejection Fraction.

Am J Med 2021 03 18;134(3):374-382. Epub 2020 Aug 18.

Department of Medicine, Weill Cornell Medicine, New York, NY. Electronic address:

Background: Complex medication regimens, often present in heart failure with preserved ejection fraction, may increase the risk of adverse drug effects and harm. We sought to characterize this complexity by determining the prevalence of polypharmacy, potentially inappropriate medications, and therapeutic competition (where a medication for 1 condition may worsen another condition) in 1 of the few dedicated heart failure with preserved ejection fraction programs in the United States.

Methods: We conducted chart review on 231 patients with heart failure with preserved ejection fraction seen in the University of Michigan's Heart Failure with Preserved Ejection Fraction Clinic between July 2016 and September 2019. We recorded: 1) standing medications to determine the presence of polypharmacy, defined as ≥10 medications; 2) potentially inappropriate medications based on the 2016 American Heart Association Scientific Statement on drugs that pose a major risk of causing or exacerbating heart failure, the 2019 Beers Criteria update, or a previously described list of medications associated with geriatric syndromes; and 3) competing conditions and subsequent medications that could create therapeutic competition.

Results: The prevalence of polypharmacy was 74%, and the prevalence of potentially inappropriate medications was 100%. Competing conditions were present in 81% of patients, of whom 49% took a medication that created therapeutic competition.

Conclusion: In addition to confirming that polypharmacy was highly prevalent, we found that potentially inappropriate medications and therapeutic competition were also frequently present. This supports the urgent need to develop patient-centered approaches to mitigate the negative effects of complex medication regimens endemic to adults with heart failure with preserved ejection fraction.
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http://dx.doi.org/10.1016/j.amjmed.2020.07.023DOI Listing
March 2021

GWAS of thyroid stimulating hormone highlights pleiotropic effects and inverse association with thyroid cancer.

Nat Commun 2020 08 7;11(1):3981. Epub 2020 Aug 7.

Center for Statistical Genetics and Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan, USA.

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.
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http://dx.doi.org/10.1038/s41467-020-17718-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414135PMC
August 2020

Gait speed is a preoperative indicator of postoperative events after elective proximal aortic surgery.

J Thorac Cardiovasc Surg 2020 May 23. Epub 2020 May 23.

University of Michigan, Michigan Medicine, Ann Arbor, Mich; Department of Cardiac Surgery, Michigan Medicine, Ann Arbor, Mich. Electronic address:

Objective: The study objective was to evaluate whether 5-m gait speed, an established marker of frailty, is associated with postoperative events after elective proximal aortic surgery.

Methods: We performed a retrospective review of 435 patients aged more than 60 years who underwent elective proximal aortic surgery, defined as surgery on the aortic root, ascending aorta, or aortic arch through median sternotomy. Patients completed a 5-m gait speed test within 30 days before surgery. We evaluated the association between categoric (slow, ≤0.83 m/s and normal, >0.83 m/s) and continuous gait speed and the likelihood of experiencing the composite outcome before and after adjustment for European System for Cardiac Operative Risk Evaluation II. The composite outcome included in-hospital mortality, renal failure, prolonged ventilation, and discharge location. Secondary outcomes were 1-year mortality and 5-year survival.

Results: Of the study population, 30.3% (132/435) were categorized as slow. Slow walkers were significantly more likely to have in-hospital mortality, prolonged ventilation, and renal failure, and were less likely to be discharged home (all P < .05). The composite outcome was 2 times more likely to occur for slow walkers (gait speed categoric adjusted odds ratio, 2.08; 95% confidence interval, 1.27-3.40; P = .004). Moreover, a unit (1 m/s) increase in gait speed (continuous) was associated with 73% lower risk of experiencing the composite outcome (odds ratio, 0.27; 95% confidence interval, 0.11-0.68; P = .006).

Conclusions: Slow gait speed is a preoperative indicator of risk for postoperative events after elective proximal aortic surgery. Gait speed may be an important tool to complement existing operative risk models, and its application may identify patients who may benefit from presurgical and postsurgical rehabilitation.
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http://dx.doi.org/10.1016/j.jtcvs.2020.03.165DOI Listing
May 2020

Age-of-onset information helps identify 76 genetic variants associated with allergic disease.

PLoS Genet 2020 06 30;16(6):e1008725. Epub 2020 Jun 30.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Risk factors that contribute to inter-individual differences in the age-of-onset of allergic diseases are poorly understood. The aim of this study was to identify genetic risk variants associated with the age at which symptoms of allergic disease first develop, considering information from asthma, hay fever and eczema. Self-reported age-of-onset information was available for 117,130 genotyped individuals of European ancestry from the UK Biobank study. For each individual, we identified the earliest age at which asthma, hay fever and/or eczema was first diagnosed and performed a genome-wide association study (GWAS) of this combined age-of-onset phenotype. We identified 50 variants with a significant independent association (P<3x10-8) with age-of-onset. Forty-five variants had comparable effects on the onset of the three individual diseases and 38 were also associated with allergic disease case-control status in an independent study (n = 222,484). We observed a strong negative genetic correlation between age-of-onset and case-control status of allergic disease (rg = -0.63, P = 4.5x10-61), indicating that cases with early disease onset have a greater burden of allergy risk alleles than those with late disease onset. Subsequently, a multivariate GWAS of age-of-onset and case-control status identified a further 26 associations that were missed by the univariate analyses of age-of-onset or case-control status only. Collectively, of the 76 variants identified, 18 represent novel associations for allergic disease. We identified 81 likely target genes of the 76 associated variants based on information from expression quantitative trait loci (eQTL) and non-synonymous variants, of which we highlight ADAM15, FOSL2, TRIM8, BMPR2, CD200R1, PRKCQ, NOD2, SMAD4, ABCA7 and UBE2L3. Our results support the notion that early and late onset allergic disease have partly distinct genetic architectures, potentially explaining known differences in pathophysiology between individuals.
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http://dx.doi.org/10.1371/journal.pgen.1008725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367489PMC
June 2020

Use of a Polygenic Risk Score Improves Prediction of Myocardial Injury After Non-Cardiac Surgery.

Circ Genom Precis Med 2020 08 9;13(4):e002817. Epub 2020 Jun 9.

Department of Anesthesiology, Michigan Medicine, Ann Arbor (N.J.D., A.L., C.M.B., S.K., M.E., M.R.M.).

Background: While postoperative myocardial injury remains a major driver of morbidity and mortality, the ability to accurately identify patients at risk remains limited despite decades of clinical research. The role of genetic information in predicting myocardial injury after noncardiac surgery (MINS) remains unknown and requires large scale electronic health record and genomic data sets.

Methods: In this retrospective observational study of adult patients undergoing noncardiac surgery, we defined MINS as new troponin elevation within 30 days following surgery. To determine the incremental value of polygenic risk score (PRS) for coronary artery disease, we added the score to 3 models of MINS risk: revised cardiac risk index, a model comprised entirely of preoperative variables, and a model with combined preoperative plus intraoperative variables. We assessed performance without and with PRSs via area under the receiver operating characteristic curve and net reclassification index.

Results: Among 90 053 procedures across 40 498 genotyped individuals, we observed 429 cases with MINS (0.5%). PRS for coronary artery disease was independently associated with MINS for each multivariable model created (odds ratio=1.12 [95% CI, 1.02-1.24], =0.023 in the revised cardiac risk index-based model; odds ratio, 1.19 [95% CI, 1.07-1.31], =0.001 in the preoperative model; and odds ratio, 1.17 [95% CI, 1.06-1.30], =0.003 in the preoperative plus intraoperative model). The addition of clinical risk factors improved model discrimination. When PRS was included with preoperative and preoperative plus intraoperative models, up to 3.6% of procedures were shifted into a new outcome classification.

Conclusions: The addition of a PRS does not significantly improve discrimination but remains independently associated with MINS and improves goodness of fit. As genetic analysis becomes more common, clinicians will have an opportunity to use polygenic risk to predict perioperative complications. Further studies are necessary to determine if PRSs can inform MINS surveillance.
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http://dx.doi.org/10.1161/CIRCGEN.119.002817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442662PMC
August 2020

Scalable generalized linear mixed model for region-based association tests in large biobanks and cohorts.

Nat Genet 2020 06 18;52(6):634-639. Epub 2020 May 18.

Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI, USA.

With very large sample sizes, biobanks provide an exciting opportunity to identify genetic components of complex traits. To analyze rare variants, region-based multiple-variant aggregate tests are commonly used to increase power for association tests. However, because of the substantial computational cost, existing region-based tests cannot analyze hundreds of thousands of samples while accounting for confounders such as population stratification and sample relatedness. Here we propose a scalable generalized mixed-model region-based association test, SAIGE-GENE, that is applicable to exome-wide and genome-wide region-based analysis for hundreds of thousands of samples and can account for unbalanced case-control ratios for binary traits. Through extensive simulation studies and analysis of the HUNT study with 69,716 Norwegian samples and the UK Biobank data with 408,910 White British samples, we show that SAIGE-GENE can efficiently analyze large-sample data (N > 400,000) with type I error rates well controlled.
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http://dx.doi.org/10.1038/s41588-020-0621-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871731PMC
June 2020
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