scholarly journals Ancestrally and Temporally Diverse Analysis of Penetrance of Clinical Variants in 72,434 Individuals

2021 ◽  
Author(s):  
Iain S. Forrest ◽  
Kumardeep Chaudhary ◽  
Ha My T. Vy ◽  
Shantanu Bafna ◽  
Daniel M. Jordan ◽  
...  
Keyword(s):  
Large Scale ◽  
Disease Risk ◽  
Sequence Data ◽  
Genomic Medicine ◽  
Population Based ◽  
Loss Of Function ◽  
Pathogenic Variants ◽  
Scale Population ◽  
Predisposition Genes ◽  
Disease Predisposition

ABSTRACTA major goal of genomic medicine is to quantify the disease risk of genetic variants. Here, we report the penetrance of 37,772 clinically relevant variants (including those reported in ClinVar1 and of loss-of-function consequence) for 197 diseases in an analysis of exome sequence data for 72,434 individuals over five ancestries and six decades of ages from two large-scale population-based biobanks (BioMe Biobank and UK Biobank). With a high-quality set of 5,359 clinically impactful variants, we evaluate disease prevalence in carriers and non-carriers to interrogate major determinants and implications of penetrance. First, we associate biomarker levels with penetrance of variants in known disease-predisposition genes and illustrate their clear biological link to disease. We then systematically uncover large numbers of ClinVar pathogenic variants that confer low risk of disease, even among those reviewed by experts, while delineating stark differences in variant penetrance by molecular consequence. Furthermore, we ascertain numerous variants present in non-European ancestries and reveal how increasing carrier age modifies penetrance estimates. Lastly, we examine substantial heterogeneity of penetrance among variants in known disease-predisposition genes for conditions such as familial hypercholesterolemia and breast cancer. These data indicate that existing categorical systems for variant classification do not adequately capture disease risk and warrant consideration of a more quantitative system based on population-based penetrance to evaluate clinical impact.

scholarly journals Beyond the Brain

Stroke ◽  
2020 ◽  
Vol 51 (10) ◽  
pp. 3007-3017
Author(s):  
Kristiina Rannikmäe ◽  
David E. Henshall ◽  
Sophie Thrippleton ◽  
Qiu Ginj Kong ◽  
Mike Chong ◽  
...  
Keyword(s):  
Transient Ischemic Attack ◽  
Large Scale ◽  
Small Vessel Disease ◽  
Population Based ◽  
Pathogenic Variant ◽  
Pathogenic Variants ◽  
Scale Population ◽  
Underlying Mechanisms ◽  
Ischemic Attack ◽  
Meta Analyses

Background and Purpose: An important minority of cerebral small vessel disease (cSVD) is monogenic. Many monogenic cSVD genes are recognized to be associated with extracerebral phenotypes. We assessed the frequency of these phenotypes in existing literature. Methods: We performed a systematic review following the PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses), searching Medline/Embase for publications describing individuals with pathogenic variants in COL4A1/2 , TREX1 , HTRA1 , ADA2 , and CTSA genes (PROSPERO 74804). We included any publication reporting on ≥1 individual with a pathogenic variant and their clinically relevant phenotype. We extracted individuals’ characteristics and information about associated extracerebral phenotypes and stroke/transient ischemic attack. We noted any novel extracerebral phenotypes and looked for shared phenotypes between monogenic cSVDs. Results: After screening 6048 publications, we included 96 COL4A1 (350 individuals), 32 TREX1 (115 individuals), 43 HTRA1 (38 homozygous/61 heterozygous individuals), 16 COL4A2 (37 individuals), 119 ADA2 (209 individuals), and 3 CTSA (14 individuals) publications. The majority of individuals originated from Europe/North America, except for HTRA1 , where most were from Asia. Age varied widely, ADA2 individuals being youngest and heterozygous HTRA1/CTSA individuals oldest. Sex distribution appeared equal. Extracerebral phenotypes were common: 14% to 100% of individuals with a pathogenic variant manifested at least one extracerebral phenotype (14% COL4A2 , 43% HTRA1 heterozygotes, 47% COL4A1 , 57% TREX1 , 91% ADA2 , 94% HTRA1 homozygotes, and 100% CTSA individuals). Indeed, for 4 of 7 genes, an extracerebral phenotype was observed more frequently than stroke/transient ischemic attack. Ocular, renal, hepatic, muscle, and hematologic systems were each involved in more than one monogenic cSVD. Conclusions: Extracerebral phenotypes are common in monogenic cSVD with extracerebral system involvement shared between genes. However, inherent biases in the existing literature mean that further data from large-scale population-based longitudinal studies collecting health outcomes in a systematic unbiased way is warranted. The emerging knowledge will help to select patients for testing, inform clinical management, and provide further insights into the underlying mechanisms of cSVD.

Abstract 14629: Rare Variants for Electrocardiographic Traits Identify Arrhythmia Susceptibility Genes

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Sean J Jurgens ◽  
Seung Hoan Choi ◽  
Christopher M Haggerty ◽  
Amelia W Hall ◽  
Jennifer Halford ◽  
...  
Keyword(s):  
Rare Variants ◽  
Sequence Data ◽  
Low Frequency ◽  
Population Based ◽  
P Wave ◽  
Cardiac Conduction ◽  
Incomplete Penetrance ◽  
Loss Of Function ◽  
Discovery Sample ◽  
Pathogenic Variants

Introduction: Electrocardiogram (ECG) intervals are quantitative and heritable endophenotypes for arrhythmias and sudden cardiac death (SCD). Studying rare sequence variation related to ECG intervals may help identify the genetic underpinnings of cardiac conduction and SCD. Methods: Using a discovery sample of 29,000 individuals with whole-genome sequences from TOPMed and a replication sample of about 100,000 individuals with whole-exome sequence data from the UK Biobank and MyCode, we examined associations between low-frequency (MAF<1%) and rare (MAF<0.1%) coding variants with 5 routinely ascertained ECG intervals (RR, P-wave, PR, QRS, and QTc intervals). We further assessed pathogenic variants in identified genes using ClinVar. Results: In low-frequency single variant analysis, we observed associations for PR interval in PAM ( P =2x10 -7 ) and MFGE8 ( P =5x10 -8 ). In gene-based tests, we identified rare coding variation associated with marked effects in established SCD genes KCNQ1, KCNH2, SCN5A and KCNE1 . For example, loss-of-function or pathogenic variants in KCNQ1 and KCNH2 were carried in 0.2% of individuals, were associated with 29 ms longer QTc intervals ( P =2x10 -82 ) and conferred up to 23-fold increased odds of marked QTc prolongation ( P =4x10 -25 ). Nevertheless, over 75% of carriers had normal QTc intervals. Similarly, loss-of-function or pathogenic variants in SCN5A , carried by 0.1% of individuals, conferred marked PR prolongation (31 ms), yet less than 30% of carriers had first-degree atrioventricular block. Discussion: This study demonstrates the value of studying ECGs in large sequenced biobanks for identifying rare variants predisposing to cardiac arrhythmias. Results define the frequency of pathogenic variation in SCD genes in the population and document incomplete penetrance of such variation. Our findings may serve as a benchmark for future population-based analyses aimed at discovering clinically actionable variants and genes.

scholarly journals Whole exome sequencing and characterization of coding variation in 49,960 individuals in the UK Biobank

2019 ◽  
Author(s):  
Cristopher V. Van Hout ◽  
Ioanna Tachmazidou ◽  
Joshua D. Backman ◽  
Joshua X. Hoffman ◽  
Bin Ye ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Large Scale ◽  
Sequence Data ◽  
Varicose Veins ◽  
Large Population ◽  
Uk Biobank ◽  
Loss Of Function ◽  
Phenotypic Data ◽  
Pathogenic Variants ◽  
The Uk

SUMMARYThe 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 first tranche of large-scale exome sequence data for 49,960 study participants, revealing approximately 4 million coding variants (of which ~98.4% have frequency < 1%). The data includes 231,631 predicted loss of function variants, a >10-fold increase compared to imputed sequence for the same participants. Nearly all genes (>97%) had ≥1 predicted loss of function carrier, and most genes (>69%) had ≥10 loss of function carriers. We illustrate the power of characterizing loss of function variation in this large population through association analyses across 1,741 phenotypes. In addition to replicating a range of established associations, we discover novel loss of function 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 significance in this population, finding that 2% of the population has a medically actionable variant. Additionally, we leverage the phenotypic data to characterize the relationship between rare BRCA1 and BRCA2 pathogenic variants and cancer risk. Exomes from the first 49,960 participants are now made accessible to the scientific community and highlight the promise offered by genomic sequencing in large-scale population-based studies.

scholarly journals Investigation of monogenic causes of familial breast cancer: data from the BEACCON case-control study

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Na Li ◽  
Belle W. X. Lim ◽  
Ella R. Thompson ◽  
Simone McInerny ◽  
Magnus Zethoven ◽  
...  
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Candidate Genes ◽  
Familial Aggregation ◽  
Loss Of Function ◽  
Cancer Data ◽  
Pathogenic Variants ◽  
New Genes ◽  
Predisposing Genes ◽  
Predisposition Genes

AbstractBreast cancer (BC) has a significant heritable component but the genetic contribution remains unresolved in the majority of high-risk BC families. This study aims to investigate the monogenic causes underlying the familial aggregation of BC beyond BRCA1 and BRCA2, including the identification of new predisposing genes. A total of 11,511 non-BRCA familial BC cases and population-matched cancer-free female controls in the BEACCON study were investigated in two sequencing phases: 1303 candidate genes in up to 3892 cases and controls, followed by validation of 145 shortlisted genes in an additional 7619 subjects. The coding regions and exon–intron boundaries of all candidate genes and 14 previously proposed BC genes were sequenced using custom designed sequencing panels. Pedigree and pathology data were analysed to identify genotype-specific associations. The contribution of ATM, PALB2 and CHEK2 to BC predisposition was confirmed, but not RAD50 and NBN. An overall excess of loss-of-function (LoF) (OR 1.27, p = 9.05 × 10−9) and missense (OR 1.27, p = 3.96 × 10−73) variants was observed in the cases for the 145 candidate genes. Leading candidates harbored LoF variants with observed ORs of 2–4 and individually accounted for no more than 0.79% of the cases. New genes proposed by this study include NTHL1, WRN, PARP2, CTH and CDK9. The new candidate BC predisposition genes identified in BEACCON indicate that much of the remaining genetic causes of high-risk BC families are due to genes in which pathogenic variants are both very rare and convey only low to moderate risk.

scholarly journals Publisher Correction: A link between appendectomy and gastrointestinal cancers: a large-scale population-based cohort study in Korea

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Youn Young Park ◽  
Kil‑yong Lee ◽  
Seong Taek Oh ◽  
Sang Hyun Park ◽  
Kyung Do Han ◽  
...  
Keyword(s):  
Cohort Study ◽  
Large Scale ◽  
Population Based ◽  
Gastrointestinal Cancers ◽  
Scale Population

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

scholarly journals Maternal adherence to micronutrient supplementation before and during pregnancy in Northwest China: a large-scale population-based cross-sectional survey

BMJ Open ◽  
2019 ◽  
Vol 9 (8) ◽  
pp. e028843 ◽  
Author(s):  
Danmeng Liu ◽  
Yue Cheng ◽  
Shaonong Dang ◽  
Duolao Wang ◽  
Yaling Zhao ◽  
...  
Keyword(s):  
Pregnant Women ◽  
Large Scale ◽  
Northwest China ◽  
Population Based ◽  
Shaanxi Province ◽  
Micronutrient Supplementation ◽  
Cross Sectional Survey ◽  
Start Time ◽  
Cross Sectional ◽  
Scale Population

ObjectivesTo report the situation of maternal micronutrient supplementation before and during pregnancy in Northwest China and to examine the rates of and factors related to the adherence to micronutrient supplementation among pregnant women in this region, where dietary micronutrient intake is commonly insufficient.DesignA large-scale population-based cross-sectional survey.SettingTwenty counties and ten districts of Shaanxi Province.ParticipantsA sample of 30 027 women were selected using a stratified multistage random sampling method. A total of 28 678 women were chosen for the final analysis after excluding those who did not provide clear information about nutritional supplementation before and during pregnancy.Main outcome measuresMaternal adherence to micronutrient supplementation (high and low) were the outcomes. They were determined by the start time and duration of use according to Chinese guidelines (for folic acid (FA) supplements) and WHO recommendations (for iron, calcium and multiple-micronutrient (MMN) supplements).ResultsIn total, 83.9% of women took at least one kind of micronutrient supplement before or during pregnancy. FA (67.6%) and calcium (57.5%) were the primarily used micronutrient supplements; few participants used MMN (14.0%) or iron (5.4%). Adherence to supplementation of all micronutrients was low (7.4% for FA, 0.6% for iron, 11.7% for calcium and 2.7% for MMN). Higher educational levels, higher income levels, urban residence and better antenatal care (including pregnancy consultation and a higher frequency of antenatal visits) were associated with high adherence to micronutrient supplementation.ConclusionMaternal micronutrient supplementation before and during pregnancy in Northwest China was way below standards recommended by the Chinese guidelines or WHO. Targeted health education and future nutritional guidelines are suggested to improve this situation, especially in pregnant women with disadvantaged sociodemographic conditions.

Intolerance to environmental chemicals and sounds in irritable bowel syndrome: Explained by central sensitization?

2016 ◽  
Vol 23 (10) ◽  
pp. 1367-1377 ◽  
Author(s):  
Linnea Ståhlberg ◽  
Eva Palmquist ◽  
Steven Nordin
Keyword(s):  
Irritable Bowel Syndrome ◽  
Traumatic Stress ◽  
Large Scale ◽  
Population Based ◽  
Environmental Chemicals ◽  
Post Traumatic Stress ◽  
Scale Population ◽  
Post Traumatic ◽  
Irritable Bowel ◽  
Behavioral Disruptions

This study tested the hypotheses of irritable bowel syndrome showing (1) comorbidity with chemical and sound intolerance, other types of functionally somatic syndromes, and psychiatric disorders and (2) stronger than normal affective reactions to and behavioral disruptions from odorous/pungent chemicals and sounds in daily life. These hypotheses were tested by means of data from a large-scale population-based questionnaire study. The results showed comorbidity in irritable bowel syndrome with chemical and sound intolerance, fibromyalgia, migraine, post-traumatic stress disorder, generalized anxiety disorder, panic syndrome, and depression as well as strong reactions/disruptions from odorous/pungent chemicals and sounds in irritable bowel syndrome.

scholarly journals Combined effects of host genetics and diet on human gut microbiota and incident disease in a single population cohort

2020 ◽  
Author(s):  
Youwen Qin ◽  
Aki S Havulinna ◽  
Yang Liu ◽  
Pekka Jousilahti ◽  
Scott C Ritchie ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Microbial Communities ◽  
Large Scale ◽  
Genome Wide Association Study ◽  
Dietary Habits ◽  
Population Based ◽  
Genome Wide ◽  
Scale Population ◽  
Important Health ◽  
Disease Analysis

Co-evolution between humans and the microbial communities colonizing them has resulted in an intimate assembly of thousands of microbial species mutualistically living on and in their body and impacting multiple aspects of host physiology and health. Several studies examining whether human genetic variation can affect gut microbiota suggest a complex combination of environmental and host factors. Here, we leverage a single large-scale population-based cohort of 5,959 genotyped individuals with matched gut microbial shotgun metagenomes, dietary information and health records up to 16 years post-sampling, to characterize human genetic variations associated with microbial abundances, and predict possible causal links with various diseases using Mendelian randomization (MR). Genome-wide association study (GWAS) identified 583 independent SNP-taxon associations at genome-wide significance (p<5.0×10-8), which included notable strong associations with LCT (p=5.02×10-35), ABO (p=1.1×10-12), and MED13L (p=1.84×10-12). A combination of genetics and dietary habits was shown to strongly shape the abundances of certain key bacterial members of the gut microbiota, and explain their genetic association. Genetic effects from the LCT locus on Bifidobacterium and three other associated taxa significantly differed according to dairy intake. Variation in mucin-degrading Faecalicatena lactaris abundances were associated with ABO, highlighting a preferential utilization of secreted A/B/AB-antigens as energy source in the gut, irrespectively of fibre intake. Enterococcus faecalis levels showed a robust association with a variant in MED13L, with putative links to colorectal cancer. Finally, we identified putative causal relationships between gut microbes and complex diseases using MR, with a predicted effect of Morganella on major depressive disorder that was consistent with observational incident disease analysis. Overall, we present striking examples of the intricate relationship between humans and their gut microbial communities, and highlight important health implications.

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