scholarly journals Trans-ethnic analysis reveals genetic and non-genetic associations with COVID-19 susceptibility and severity

2020 ◽  
Author(s):  
Janie F. Shelton ◽  
Anjali J. Shastri ◽  
Chelsea Ye ◽  
Catherine H. Weldon ◽  
Teresa Filshtein-Somnez ◽  
...  
Keyword(s):  
Association Studies ◽  
Economic Status ◽  
Strong Association ◽  
Significant Risk ◽  
Significant Risk Factor ◽  
Blood Type ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Genetic Associations ◽  
Wide Range

COVID-19 presents with a wide range of severity, from asymptomatic in some individuals to fatal in others. Based on a study of over one million 23andMe research participants, we report genetic and non-genetic associations with testing positive for COVID-19, respiratory symptoms, and hospitalization. Risk factors for hospitalization include advancing age, male sex, elevated body mass index, lower socio-economic status, non-European ancestry, and pre-existing cardio-metabolic and respiratory conditions. Using trans-ethnic genome-wide association studies, we identify a strong association between blood type and COVID-19 diagnosis, as well as a gene-rich locus on chr3p21.31 that is more strongly associated with outcome severity. While non-European ancestry was found to be a significant risk factor for hospitalization after adjusting for socio-demographics and pre-existing health conditions, we did not find evidence that these two primary genetic associations explain differences between populations in terms of risk for severe COVID-19 outcomes.

Strong Association between Serotonin Transporter 5-HTTVNTR Variant and Psychoactive Substance (Nicotine) Use in the Turkish Cypriot Population

2020 ◽  
Vol 21 (6) ◽  
pp. 466-470
Author(s):  
Emine Kandemis ◽  
Gulten Tuncel ◽  
Ozen Asut ◽  
Sehime G. Temel ◽  
Mahmut C. Ergoren
Keyword(s):  
Serotonin Transporter ◽  
Association Studies ◽  
Strong Association ◽  
Smoking Behavior ◽  
Population Based ◽  
Genome Wide Association Studies ◽  
Genotype Distribution ◽  
Psychological Traits ◽  
Wide Range ◽  
Turkish Cypriot

Background: The use of psychoactive substances is one of the most dangerous social problems worldwide. Nicotine dependence results from the interaction between neurobiological, environmental and genetic factors. Serotonin is a neurotransmitter that has a wide range of central nervous system activities. The serotonin transporter gene has been previously linked to psychological traits. Objective: A variable number of tandem repeats within the serotonin transporter-linked polymorphic gene region are believed to alter the transcriptional efficiency of the 5-HTT gene. Therefore, we aimed to investigate the association between this polymorphic site and smoking behavior in the Turkish Cypriot population. Methods: A total of 259 (100 smokers, 100 non-smokers and 59 ex-smokers) Turkish Cypriots were included in this population-based cross-sectional study. Genomic DNA was extracted from peripheral blood samples and the 5-HTTVNTR2 polymorphisms were determined by the PCR-RFLP. Results: The allelic frequency and genotype distribution results of this study showed a strong association (P<0.0001) between smokers and non-smokers. No statistical significance was found between non-smokers and ex-smokers. Conclusion: This is the first genetic epidemiology study to investigate the allelic frequencies of 5-HTTVNTR2 polymorphisms associated with smoking behavior in the Turkish Cypriot population. Based on the results of this study, genome-wide association studies should be designed for preventive medicine in this population.

scholarly journals Assessment of Polygenic Architecture and Risk Prediction based on Common Variants Across Fourteen Cancers

2019 ◽  
Author(s):  
Yan Zhang ◽  
Amber N. Wilcox ◽  
Haoyu Zhang ◽  
Parichoy Pal Choudhury ◽  
Douglas F. Easton ◽  
...  
Keyword(s):  
Association Studies ◽  
Disease Incidence ◽  
Effect Sizes ◽  
European Ancestry ◽  
Risk Scores ◽  
Average Risk ◽  
Genome Wide Association Studies ◽  
Lymphoid Leukemia ◽  
Polygenic Risk ◽  
Wide Range

AbstractWe analyzed summary-level data from genome-wide association studies (GWAS) of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) contributing to risk, as well as the distribution of their associated effect sizes. All cancers evaluated showed polygenicity, involving at a minimum thousands of independent susceptibility variants. For some malignancies, particularly chronic lymphoid leukemia (CLL) and testicular cancer, there are a larger proportion of variants with larger effect sizes than those for other cancers. In contrast, most variants for lung and breast cancers have very small associated effect sizes. For different cancer sites, we estimate a wide range of GWAS sample sizes, required to explain 80% of GWAS heritability, varying from 60,000 cases for CLL to over 1,000,000 cases for lung cancer. The maximum relative risk achievable for subjects at the 99th risk percentile of underlying polygenic risk scores, compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that polygenic risk scores have substantial potential for risk stratification for relatively common cancers such as breast, prostate and colon, but limited potential for other cancer sites because of modest heritability and lower disease incidence.

scholarly journals Evidence for specificity of polygenic contributions to attainment in English, maths and science during adolescence

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Georgina Donati ◽  
Iroise Dumontheil ◽  
Oliver Pain ◽  
Kathryn Asbury ◽  
Emma L. Meaburn
Keyword(s):  
Association Studies ◽  
Genome Wide Association Studies ◽  
Genetic Associations ◽  
Parents And Children ◽  
Genome Wide ◽  
Wide Range ◽  
Gene Level ◽  
Significant Single Nucleotide Polymorphism ◽  
Genetic Contributions ◽  
Critical Developmental Period

AbstractHow well one does at school is predictive of a wide range of important cognitive, socioeconomic, and health outcomes. The last few years have shown marked advancement in our understanding of the genetic contributions to, and correlations with, academic attainment. However, there exists a gap in our understanding of the specificity of genetic associations with performance in academic subjects during adolescence, a critical developmental period. To address this, the Avon Longitudinal Study of Parents and Children was used to conduct genome-wide association studies of standardised national English (N = 5983), maths (N = 6017) and science (N = 6089) tests. High SNP-based heritabilities (h2SNP) for all subjects were found (41–53%). Further, h2SNP for maths and science remained after removing shared variance between subjects or IQ (N = 3197–5895). One genome-wide significant single nucleotide polymorphism (rs952964, p = 4.86 × 10–8) and four gene-level associations with science attainment (MEF2C, BRINP1, S100A1 and S100A13) were identified. Rs952964 remained significant after removing the variance shared between academic subjects. The findings highlight the benefits of using environmentally homogeneous samples for genetic analyses and indicate that finer-grained phenotyping will help build more specific biological models of variance in learning processes and abilities.

scholarly journals XGMix: Local-Ancestry Inference with Stacked XGBoost

2020 ◽  
Author(s):  
Arvind Kumar ◽  
Daniel Mas Montserrat ◽  
Carlos Bustamante ◽  
Alexander Ioannidis
Keyword(s):  
Association Studies ◽  
Genomic Medicine ◽  
Genetic Association Studies ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Genetic Associations ◽  
Local Ancestry ◽  
Genome Wide ◽  
Health Burdens ◽  
Local Ancestry Inference

AbstractGenomic medicine promises increased resolution for accurate diagnosis, for personalized treatment, and for identification of population-wide health burdens at rapidly decreasing cost (with a genotype now cheaper than an MRI and dropping). The benefits of this emerging form of affordable, data-driven medicine will accrue predominantly to those populations whose genetic associations have been mapped, so it is of increasing concern that over 80% of such genome-wide association studies (GWAS) have been conducted solely within individuals of European ancestry [1]. The severe under-representation of the majority of the world’s populations in genetic association studies stems in part from an addressable algorithmic weakness: lack of simple, accurate, and easily trained methods for identifying and annotating ancestry along the genome (local ancestry). Here we present such a method (XGMix) based on gradient boosted trees, which, while being accurate, is also simple to use, and fast to train, taking minutes on consumer-level laptops.

scholarly journals Systematic single-variant and gene-based association testing of 3,700 phenotypes in 281,850 UK Biobank exomes

2021 ◽  
Author(s):  
Konrad Karczewski ◽  
Matthew Solomonson ◽  
Katherine R Chao ◽  
Julia K Goodrich ◽  
Grace Tiao ◽  
...  
Keyword(s):  
Sequence Data ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Uk Biobank ◽  
Genetic Associations ◽  
Allelic Series ◽  
Association Analyses ◽  
Wide Range ◽  
The Uk ◽  
The Impact

Genome-wide association studies have successfully discovered thousands of common variants associated with human diseases and traits, but the landscape of rare variation in human disease has not been explored at scale. Exome sequencing studies of population biobanks provide an opportunity to systematically evaluate the impact of rare coding variation across a wide range of phenotypes to discover genes and allelic series relevant to human health and disease. Here, we present results from systematic association analyses of 3,700 phenotypes using single-variant and gene tests of 281,850 individuals in the UK Biobank with exome sequence data. We find that the discovery of genetic associations is tightly linked to frequency as well as correlated with metrics of deleteriousness and natural selection. We highlight biological findings elucidated by these data and release the dataset as a public resource alongside a browser framework for rapidly exploring rare variant association results.

scholarly journals Beyond power: Multivariate discovery, replication, and interpretation of pleiotropic loci using summary association statistics

2015 ◽  
Author(s):  
Zheng Ning ◽  
Yakov A. Tsepilov ◽  
Sodbo Zh. Sharapov ◽  
Alexander K. Grishenko ◽  
Xiao Feng ◽  
...  
Keyword(s):  
Open Source ◽  
Genetic Variants ◽  
Association Studies ◽  
R Package ◽  
Genetic Effects ◽  
Pleiotropic Effects ◽  
Genome Wide Association Studies ◽  
Genetic Associations ◽  
Study Results ◽  
Wide Range

AbstractThe ever-growing genome-wide association studies (GWAS) have revealed widespread pleiotropy. To exploit this, various methods which consider variant association with multiple traits jointly have been developed. However, most effort has been put on improving discovery power: how to replicate and interpret these discovered pleiotropic loci using multivariate methods has yet to be discussed fully. Using only multiple publicly available single-trait GWAS summary statistics, we develop a fast and flexible multi-trait framework that contains modules for (i) multi-trait genetic discovery, (ii) replication of locus pleiotropic profile, and (iii) multi-trait conditional analysis. The procedure is able to handle any level of sample overlap. As an empirical example, we discovered and replicated 23 novel pleiotropic loci for human anthropometry and evaluated their pleiotropic effects on other traits. By applying conditional multivariate analysis on the 23 loci, we discovered and replicated two additional multi-trait associated SNPs. Our results provide empirical evidence that multi-trait analysis allows detection of additional, replicable, highly pleiotropic genetic associations without genotyping additional individuals. The methods are implemented in a free and open source R package MultiABEL.Author summaryBy analyzing large-scale genomic data, geneticists have revealed widespread pleiotropy, i.e. single genetic variation can affect a wide range of complex traits. Methods have been developed to discover such genetic variants. However, we still lack insights into the relevant genetic architecture - What more can we learn from knowing the effects of these genetic variants?Here, we develop a fast and flexible statistical analysis procedure that includes discovery, replication, and interpretation of pleiotropic effects. The whole analysis pipeline only requires established genetic association study results. We also provide the mathematical theory behind the pleiotropic genetic effects testing.Most importantly, we show how a replication study can be essential to reveal new biology rather than solely increasing sample size in current genomic studies. For instance, we show that, using our proposed replication strategy, we can detect the difference in genetic effects between studies of different geographical origins.We applied the method to the GIANT consortium anthropometric traits to discover new genetic associations, replicated in the UK Biobank, and provided important new insights into growth and obesity.Our pipeline is implemented in an open-source R package MultiABEL, sufficiently efficient that allows researchers to immediately apply on personal computers in minutes.

scholarly journals Association between PRDM16, MEF2D, TRPM8, LRP1 gene polymorphisms and migraine susceptibility in the She ethnic population in China

2019 ◽  
Vol 42 (1) ◽  
pp. E21-E30 ◽  
Author(s):  
Xianguo Fu ◽  
Jing Yang ◽  
Xiaoyang Wu ◽  
Qifang Lin ◽  
Yuli Zeng ◽  
...  
Keyword(s):  
Association Studies ◽  
Direct Sequencing ◽  
Significant Risk ◽  
Significant Risk Factor ◽  
Han Chinese ◽  
Small Sample ◽  
Genome Wide Association Studies ◽  
Healthy Controls ◽  
Nucleotide Polymorphisms ◽  
Asian Populations

Background: The prevalence of migraines in the She population, a minority in China, is significantly higher than that in Han Chinese and other Asian populations. Two single nucleotide polymorphisms (SNPs) have been found to be associated with migraine susceptibility in the She population. Purpose: This study investigated four SNPs, identified in genome-wide association studies, within migraine-susceptible loci in Han Chinese for their association with migraine susceptibility in the She population. Methods: Two-hundred unrelated migraine patients and 200 healthy controls were recruited. The SNPs examined included rs2651899 (PRDM16 ), rs2274316 (MEF2D ), rs7577262 (TRPM8) and rs11172113 (LRP1). Genotyping of the SNPs was performed by allele-specific polymerase chain reaction and direct sequencing. Results: No significant differences between the participants with migraines and controls (participants without migraines) were demonstrated in genotypes, alleles and allele carriage frequencies for the four SNPs. A subgroup analysis found that migraine with aura had a lower frequency of C allele positivity in rs2651899 than in healthy controls (59.6% vs. 74.5%, respectively; P < 0.034). Univariate analyses indicated that no genotype of the four SNPs had a significant association with migraines. Males had a lower risk of migraines, and advanced age was a significant risk factor for migraines in females. Conclusion: The SNPs in four migraine susceptible loci in Han Chinese were not risk factors for migraines in a relatively small sample of the She population.

scholarly journals Zinc Transporter-8 Gene (SLC30A8) Is Associated with Type 2 Diabetes in Chinese

2008 ◽  
Vol 93 (10) ◽  
pp. 4107-4112 ◽  
Author(s):  
Jie Xiang ◽  
Xiao-Ying Li ◽  
Min Xu ◽  
Jie Hong ◽  
Yun Huang ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Confidence Interval ◽  
Glucose Tolerance ◽  
Association Studies ◽  
Strong Association ◽  
Insulin Response ◽  
Han Chinese ◽  
European Ancestry ◽  
Genome Wide Association Studies

Context: Several genome-wide association studies identified a strong association of SLC30A8 with type 2 diabetes in individuals of European ancestry. The effect of the association of rs13266634 with type 2 diabetes or related glycemic traits has not been fully extended to non-European populations, and a comprehensive examination of common variants in the gene has not yet been carried out in Han Chinese. Objective: The objective of the study was to investigate the association of SLC30A8 with type 2 diabetes in Chinese. Design: A comprehensive gene-based association study was performed using 14 tagging single-nucleotide polymorphism (SNPs) of SLC30A8 in Han Chinese subjects with normal glucose tolerance (NGT; n = 721), impaired glucose regulation (IGR; n = 375), and type 2 diabetes (n = 521). Results: A significant association for SNP rs13266634 was observed between patients with type 2 diabetes and NGT controls (P = 0.016). The association was also observed between combined type 2 diabetes/IGR and NGT subjects (P = 0.002). The adjusted odds ratios for homozygote CC vs. TT at this locus were 1.71 for type 2 diabetes (95% confidence interval 1.19–2.45, P = 0.002) and 1.77 for type 2 diabetes and IGR (95% confidence interval 1.29–2.42, P = 0.0001). We further studied the genotype-phenotype correlation in 70 Han Chinese using iv glucose tolerance test and found an association between SNP rs13266634 and acute insulin response to glucose and disposition index (adjusted P = 0.012 and 0.004, respectively). Conclusions: Our results provide evidence that SLC30A8 is a susceptible locus for type 2 diabetes in Chinese population, and its variant can influence insulin secretion.

scholarly journals Loss-of-function of MFGE8 and protection against coronary atherosclerosis

2021 ◽  
Author(s):  
Sanni E Ruotsalainen ◽  
Ida Surakka ◽  
Nina Mars ◽  
Juha Karjalainen ◽  
Mitja Kurki ◽  
...  
Keyword(s):  
Cardiovascular Diseases ◽  
Coronary Atherosclerosis ◽  
Association Studies ◽  
Meta Analysis ◽  
Significant Risk ◽  
Premature Death ◽  
Population History ◽  
Genome Wide Association Studies ◽  
Genetic Associations ◽  
Loss Of Function

Cardiovascular diseases are the leading cause of premature death and disability worldwide, with both genetic and environmental determinants. While genome-wide association studies have identified multiple genetic loci associated with cardiovascular diseases, exact genes driving these associations remain mostly uncovered. Due to Finland's population history, many deleterious and high-impact variants are enriched in the Finnish population giving a possibility to find genetic associations for protein-truncating variants that likely tie the association to a gene and that would not be detected elsewhere. In FinnGen, a large Finnish biobank study, we identified an inframe insertion rs534125149 in MFGE8 to have protective effect against coronary atherosclerosis (OR = 0.75, p = 2.63E-16) and related endpoints. This variant is highly enriched in Finland (70-fold compared to Non-Finnish Europeans) with allele frequency of 3% in Finland. The protective association was replicated in meta-analysis of biobanks of Japan and Estonian (OR = 0.75, p = 5.41E-7). Additionally, we identified a splice acceptor variant rs201988637 in MFGE8, independent of the rs534125149 and similarly protective in relation to coronary atherosclerosis (OR = 0.72, p = 7.94E-06) and related endpoints, with no significant risk-increasing associations. The protein-truncating variant was also associated with lower pulse pressure, pointing towards a function of MFGE8 in arterial stiffness and aging also in humans in addition to previous evidence in mice. In conclusion, our results show that inhibiting the production of lactadherin could lower the risk for coronary heart disease substantially.

scholarly journals Quantitative and Qualitative Role of Antagonistic Heterogeneity in Genetics of Blood Lipids

2019 ◽  
Vol 75 (10) ◽  
pp. 1811-1819
Author(s):  
Alexander M Kulminski ◽  
Yury Loika ◽  
Alireza Nazarian ◽  
Irina Culminskaya
Keyword(s):  
Genetic Predisposition ◽  
Complex Traits ◽  
Blood Lipids ◽  
Association Studies ◽  
Density Lipoprotein ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Genetic Associations ◽  
Trade Offs ◽  
Genome Wide

Abstract Prevailing strategies in genome-wide association studies (GWAS) mostly rely on principles of medical genetics emphasizing one gene, one function, one phenotype concept. Here, we performed GWAS of blood lipids leveraging a new systemic concept emphasizing complexity of genetic predisposition to such phenotypes. We focused on total cholesterol, low- and high-density lipoprotein cholesterols, and triglycerides available for 29,902 individuals of European ancestry from seven independent studies, men and women combined. To implement the new concept, we leveraged the inherent heterogeneity in genetic predisposition to such complex phenotypes and emphasized a new counter intuitive phenomenon of antagonistic genetic heterogeneity, which is characterized by misalignment of the directions of genetic effects and the phenotype correlation. This analysis identified 37 loci associated with blood lipids but only one locus, FBXO33, was not reported in previous top GWAS. We, however, found strong effect of antagonistic heterogeneity that leaded to profound (quantitative and qualitative) changes in the associations with blood lipids in most, 25 of 37 or 68%, loci. These changes suggested new roles for some genes, which functions were considered as well established such as GCKR, SIK3 (APOA1 locus), LIPC, LIPG, among the others. The antagonistic heterogeneity highlighted a new class of genetic associations emphasizing beneficial and adverse trade-offs in predisposition to lipids. Our results argue that rigorous analyses dissecting heterogeneity in genetic predisposition to complex traits such as lipids beyond those implemented in current GWAS are required to facilitate translation of genetic discoveries into health care.

Sign in / Sign up

Export Citation Format

Share Document