scholarly journals Accurate Genomic Prediction Of Human Height

2017 ◽  
Author(s):  
Louis Lello ◽  
Steven G. Avery ◽  
Laurent Tellier ◽  
Ana I. Vazquez ◽  
Gustavo de los Campos ◽  
...  
Keyword(s):  
Genetic Architecture ◽  
Uk Biobank ◽  
Multiple Phenotypes ◽  
Human Height ◽  
Out Of Sample ◽  
Heel Bone ◽  
The Common ◽  
Actual Height ◽  
The Uk ◽  
Missing Heritability Problem

AbstractWe construct genomic predictors for heritable and extremely complex human quan-titative traits (height, heel bone density, and educational attainment) using modern methods in high dimensional statistics (i.e., machine learning). Replication tests show that these predictors capture, respectively, ∼40, 20, and 9 percent of total variance for the three traits. For example, predicted heights correlate ∼0.65 with actual height; actual heights of most individuals in validation samples are within a few cm of the prediction. The variance captured for height is comparable to the estimated SNP heritability from GCTA (GREML) analysis, and seems to be close to its asymptotic value (i.e., as sample size goes to infinity), suggesting that we have captured most of the heritability for the SNPs used. Thus, our results resolve the common SNP portion of the “missing heritability” problem – i.e., the gap between prediction R-squared and SNP heritability. The ∼20k activated SNPs in our height predictor reveal the genetic architecture of human height, at least for common SNPs. Our primary dataset is the UK Biobank cohort, comprised of almost 500k individual genotypes with multiple phenotypes. We also use other datasets and SNPs found in earlier GWAS for out-of-sample validation of our results.

scholarly journals Homozygosity for TYK2 P1104A underlies tuberculosis in about 1% of patients in a cohort of European ancestry

2019 ◽  
Vol 116 (21) ◽  
pp. 10430-10434 ◽  
Author(s):  
Gaspard Kerner ◽  
Noe Ramirez-Alejo ◽  
Yoann Seeleuthner ◽  
Rui Yang ◽  
Masato Ogishi ◽  
...  
Keyword(s):  
Odds Ratio ◽  
Genetic Basis ◽  
Sub Saharan Africa ◽  
European Ancestry ◽  
Uk Biobank ◽  
The United Kingdom ◽  
The Common ◽  
Sub Saharan ◽  
The Uk ◽  
High Level

The human genetic basis of tuberculosis (TB) has long remained elusive. We recently reported a high level of enrichment in homozygosity for the common TYK2 P1104A variant in a heterogeneous cohort of patients with TB from non-European countries in which TB is endemic. This variant is homozygous in ∼1/600 Europeans and ∼1/5,000 people from other countries outside East Asia and sub-Saharan Africa. We report a study of this variant in the UK Biobank cohort. The frequency of P1104A homozygotes was much higher in patients with TB (6/620, 1%) than in controls (228/114,473, 0.2%), with an odds ratio (OR) adjusted for ancestry of 5.0 [95% confidence interval (CI): 1.96–10.31, P = 2 × 10−3]. Conversely, we did not observe enrichment for P1104A heterozygosity, or for TYK2 I684S or V362F homozygosity or heterozygosity. Moreover, it is unlikely that more than 10% of controls were infected with Mycobacterium tuberculosis, as 97% were of European genetic ancestry, born between 1939 and 1970, and resided in the United Kingdom. Had all of them been infected, the OR for developing TB upon infection would be higher. These findings suggest that homozygosity for TYK2 P1104A may account for ∼1% of TB cases in Europeans.

Sex differences in genetic architecture in the UK Biobank

2021 ◽  
Vol 53 (9) ◽  
pp. 1283-1289
Author(s):  
Elena Bernabeu ◽  
Oriol Canela-Xandri ◽  
Konrad Rawlik ◽  
Andrea Talenti ◽  
James Prendergast ◽  
...  
Keyword(s):  
Sex Differences ◽  
Genetic Architecture ◽  
Uk Biobank ◽  
The Uk

scholarly journals Imputation of Behavioral Candidate Gene Repeat Polymorphisms in 486,551 Publicly-Available UK Biobank Individuals

2018 ◽  
Author(s):  
Richard Border ◽  
Andrew Smolen ◽  
Robin P. Corley ◽  
Michael C. Stallings ◽  
Sandra A. Brown ◽  
...  
Keyword(s):  
Imputation Accuracy ◽  
Variable Number Tandem Repeat ◽  
Variable Number ◽  
Uk Biobank ◽  
Out Of Sample ◽  
The Subject ◽  
Polymorphism Data ◽  
The Uk ◽  
Broad Interest ◽  
Vntr Polymorphisms

AbstractSome of the most widely studied polymorphisms in psychiatric genetics include variable number tandem repeat polymorphisms (VNTRs) in SLC6A3, DRD4, SLC6A4, and MAOA. While initial findings suggested large effects, their importance with respect to psychiatric phenotypes is the subject of much debate with broadly conflicting results. Despite broad interest, these loci remain absent from the largest available samples, such as the UK Biobank, limiting researchers’ ability to test these contentious hypotheses rigorously in large samples. Here, using two independent reference datasets, we report out-of-sample imputation accuracy estimates of >0.96 for all four VNTR polymorphisms and one modifying SNP, depending on the reference and target dataset. We describe the imputation procedures of these candidate polymorphisms in 486,551 UK Biobank individuals, and have made the imputed polymorphism data available to UK Biobank researchers. This resource, provided to the community, will allow the most rigorous tests to-date of the roles of these polymorphisms in behavioral and psychiatric phenotypes.

scholarly journals ApoE e4 Genotype Predicts Severe COVID-19 in the UK Biobank Community Cohort

2020 ◽  
Author(s):  
Chia-Ling Kuo ◽  
Luke C Pilling ◽  
Janice L Atkins ◽  
Jane AH Masoli ◽  
João Delgado ◽  
...  
Keyword(s):  
Older Adults ◽  
Risk Factor ◽  
High Risk ◽  
The Novel ◽  
Shortness Of Breath ◽  
Uk Biobank ◽  
Impaired Consciousness ◽  
Homozygous Genotype ◽  
The Common ◽  
The Uk

The novel respiratory disease COVID-19 produces varying symptoms, with fever, cough, and shortness of breath being common. In older adults, we found that pre-existing dementia is a major risk factor (OR = 3.07, 95% CI: 1.71 to 5.50) for COVID-19 hospitalization in the UK Biobank (UKB). In another UK study of 16,749 patients hospitalized for COVID-19, dementia was among the common comorbidities and was associated with higher mortality. Additionally, impaired consciousness, including delirium, is common in severe cases. The ApoE e4 genotype is associated with both dementia and delirium, with the e4e4 (homozygous) genotype associated with high risk of dementia. We therefore aimed to test associations between ApoE e4 alleles and COVID-19 severity, using the UKB data.

M69 EVALUATING THE AGE-OF-ONSET-DEPENDENT GENETIC ARCHITECTURE OF COMPLEX DISORDERS IN THE UK BIOBANK

2019 ◽  
Vol 29 ◽  
pp. S203-S204
Author(s):  
Yen-Chen Anne Feng ◽  
Tian Ge ◽  
Chia-Yen Chen ◽  
Jordan Smoller ◽  
Benjamin Neale
Keyword(s):  
Genetic Architecture ◽  
Age Of Onset ◽  
Uk Biobank ◽  
Complex Disorders ◽  
The Uk

scholarly journals A global overview of genetically interpretable multimorbidities among common diseases in the UK Biobank

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Guiying Dong ◽  
Jianfeng Feng ◽  
Fengzhu Sun ◽  
Jingqi Chen ◽  
Xing-Ming Zhao
Keyword(s):  
Genetic Architecture ◽  
Hospital Inpatient ◽  
Uk Biobank ◽  
Network Decomposition ◽  
Genetic Components ◽  
Common Diseases ◽  
Cell Immunity ◽  
Genetic Risks ◽  
The Uk ◽  
Shared Genetic

Abstract Background Multimorbidities greatly increase the global health burdens, but the landscapes of their genetic risks have not been systematically investigated. Methods We used the hospital inpatient data of 385,335 patients in the UK Biobank to investigate the multimorbid relations among 439 common diseases. Post-GWAS analyses were performed to identify multimorbidity shared genetic risks at the genomic loci, network, as well as overall genetic architecture levels. We conducted network decomposition for the networks of genetically interpretable multimorbidities to detect the hub diseases and the involved molecules and functions in each module. Results In total, 11,285 multimorbidities among 439 common diseases were identified, and 46% of them were genetically interpretable at the loci, network, or overall genetic architecture levels. Multimorbidities affecting the same and different physiological systems displayed different patterns of the shared genetic components, with the former more likely to share loci-level genetic components while the latter more likely to share network-level genetic components. Moreover, both the loci- and network-level genetic components shared by multimorbidities converged on cell immunity, protein metabolism, and gene silencing. Furthermore, we found that the genetically interpretable multimorbidities tend to form network modules, mediated by hub diseases and featuring physiological categories. Finally, we showcased how hub diseases mediating the multimorbidity modules could help provide useful insights for the genetic contributors of multimorbidities. Conclusions Our results provide a systematic resource for understanding the genetic predispositions of multimorbidities and indicate that hub diseases and converged molecules and functions may be the key for treating multimorbidities. We have created an online database that facilitates researchers and physicians to browse, search, or download these multimorbidities (https://multimorbidity.comp-sysbio.org).

scholarly journals Detection and quantification of inbreeding depression for complex traits from SNP data

2017 ◽  
Vol 114 (32) ◽  
pp. 8602-8607 ◽  
Author(s):  
Loic Yengo ◽  
Zhihong Zhu ◽  
Naomi R. Wray ◽  
Bruce S. Weir ◽  
Jian Yang ◽  
...  
Keyword(s):  
Inbreeding Depression ◽  
Complex Traits ◽  
Genetic Architecture ◽  
Handgrip Strength ◽  
Uk Biobank ◽  
Snp Data ◽  
Causal Variants ◽  
Auditory Acuity ◽  
The Uk ◽  
Detection And Quantification

Quantifying the effects of inbreeding is critical to characterizing the genetic architecture of complex traits. This study highlights through theory and simulations the strengths and shortcomings of three SNP-based inbreeding measures commonly used to estimate inbreeding depression (ID). We demonstrate that heterogeneity in linkage disequilibrium (LD) between causal variants and SNPs biases ID estimates, and we develop an approach to correct this bias using LD and minor allele frequency stratified inference (LDMS). We quantified ID in 25 traits measured in ∼140,000 participants of the UK Biobank, using LDMS, and confirmed previously published ID for 4 traits. We find unique evidence of ID for handgrip strength, waist/hip ratio, and visual and auditory acuity (ID between −2.3 and −5.2 phenotypic SDs for complete inbreeding; P<0.001). Our results illustrate that a careful choice of the measure of inbreeding combined with LDMS stratification improves both detection and quantification of ID using SNP data.

scholarly journals Association of the Transthyretin Variant V122I With Polyneuropathy Among Individuals of African Descent

2020 ◽  
Author(s):  
Margaret M. Parker ◽  
Scott M. Damrauer ◽  
Catherine Tcheandjieu ◽  
David Erbe ◽  
Emre Aldinc ◽  
...  
Keyword(s):  
Cox Regression ◽  
African Descent ◽  
Gene Mutations ◽  
Uk Biobank ◽  
Cardiac Phenotype ◽  
Diagnosis Codes ◽  
Increased Risk ◽  
Tunnel Syndrome ◽  
The Common ◽  
The Uk

BACKGROUNDHereditary transthyretin-mediated (hATTR) amyloidosis is a progressively debilitating disease caused by transthyretin (TTR) gene mutations. The V122I variant, a common pathogenic TTR mutation found primarily in individuals of West African descent, is frequently associated with cardiomyopathy.METHODSThe association between the V122I variant and ICD10 diagnosis codes was assessed in the UK Biobank black subpopulation (N=6062); whether significant associations could be replicated in the Penn Medicine Biobank (N=5737) and Million Veteran Program (N=82,382) was then investigated. Cumulative incidence of common hATTR amyloidosis manifestations (polyneuropathy, carpal tunnel syndrome, cardiomyopathy, and heart failure) was estimated by V122I genotype in the UK Biobank using Cox regression controlling for age, sex, and genetic ancestry.RESULTSPhenome-wide analysis identified a significant association between V122I genotype and polyneuropathy diagnosis (odds ratio [OR]=6.4, 95% confidence interval [CI]=2.6–15.6, P=4.2×10−5) in the UK Biobank. A significant association was also observed in the Penn Medicine Biobank (OR=1.6, 95% CI=1.2–2.4, P=6.0×10−3) and the Million Veteran Program (OR=1.5, 95% CI=1.2–1.8, P=1.8×10−4). Prevalence of a polyneuropathy diagnosis among V122I carriers was 2.1%, 9.0%, and 4.8% in the UK Biobank, Penn Medicine Biobank, and Million Veteran Program, respectively. In the UK Biobank, common hATTR amyloidosis manifestations were significantly enriched in V122I carriers compared with non-carriers (HR=2.8; 95% CI=1.7–4.5; P=2.6×10−5). By age 75, 37.4% of V122I carriers had a diagnosis of any one of the common manifestations, including polyneuropathy (7.9%).CONCLUSIONSV122I carriers, historically associated with a predominantly cardiac phenotype of hATTR amyloidosis, have a significantly increased risk of polyneuropathy.

scholarly journals Coordinated Interaction: A model and test for globally signed epistasis in complex traits

2020 ◽  
Author(s):  
Brooke Sheppard ◽  
Nadav Rappoport ◽  
Po-Ru Loh ◽  
Stephan J. Sanders ◽  
Andy Dahl ◽  
...  
Keyword(s):  
Complex Traits ◽  
Genetic Architecture ◽  
Model Systems ◽  
Disease Dynamics ◽  
Uk Biobank ◽  
Biological Models ◽  
Model Sets ◽  
The Uk ◽  
Complex Human Traits ◽  
Main Effects

AbstractInteractions between genetic variants – epistasis – is pervasive in model systems and can profoundly impact evolutionary adaption, population disease dynamics, genetic mapping, and precision medicine efforts. In this work we develop a model for structured polygenic epistasis, called Coordinated Interaction (CI), and prove that several recent theories of genetic architecture fall under the formal umbrella of CI. Unlike standard polygenic epistasis models that assume interaction and main effects are independent, in the CI model, sets of SNPs broadly interact positively or negatively, on balance skewing the penetrance of main genetic effects. To test for the existence of CI we propose the even-odd (EO) test and prove it is calibrated in a range of realistic biological models. Applying the EO test in the UK Biobank, we find evidence of CI in 14 of 26 traits spanning disease, anthropometric, and blood categories. Finally, we extend the EO test to tissue-specific enrichment and identify several plausible tissue-trait pairs. Overall, CI is a new dimension of genetic architecture that can capture structured, systemic interactions in complex human traits.

Sign in / Sign up

Export Citation Format

Share Document