scholarly journals Genome-wide Discovery for Diabetes-Dependent Triglycerides-Associated Loci

2022 ◽  
Author(s):  
Margaret Sunitha Selvaraj ◽  
Kaavya Paruchuri ◽  
Sara Haidermota ◽  
Rachel Bernardo ◽  
Stephen S Rich ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Genome Wide Association Study ◽  
P Value ◽  
Significant Heterogeneity ◽  
Association Analyses ◽  
Genome Wide ◽  
The Uk ◽  
Design And Methods ◽  
Allele Count

Objective: Discover loci associated with triglyceride (TG) levels in the context of type 2 diabetes (T2D). Research Design and Methods: Genome-wide association study (GWAS) was performed in 424,120 genotyped participants of the UK Biobank (UKB) with T2D status and TG levels. Association analyses of TG levels were performed stratified by T2D status for genetic variants with minor allele count (MAC) at least 20 in each stratum. Effect differences of genetic variants by T2D status were determined by Cochrans Q-test implemented in METAL (p-value<5x10-8). Validation of significant variants was pursued in 25,137 participants of the Mass General Brigham Biobank (MGBB). Results: Among 21,176 T2D and 402,944 non-T2D samples, stratified GWAS identified 19 and 315 genomic risk loci significantly associated with TG levels, respectively. Only chr6p21.32 exhibited genome-wide significant heterogeneity (I2=98.4%; pheterogeneity=2.1x10-15), with log(TG) effect estimates of -0.066 (95%CI: -0.082, -0.050) and 0.002 (95%CI: -0.002, 0.006) for T2D and non-T2D, respectively. The lead variant rs9274619:A (allele frequency 0.095) is located 2Kb upstream of the HLA-DQB1 gene. We replicated this finding among 25,137 participants (6,951 T2D cases) of MGBB (pheterogeneity=9.5x10-3). Phenome-wide interaction association analyses showed that the lead variant was strongly associated with a concomitant diagnosis of type 1 diabetes (T1D) as well as diabetes-associated complications. Conclusion: An intergenic variant near HLA-DQB1 significantly associates with decreased triglycerides only among those with T2D and highlights an immune overlap with T1D.

Lifestyle factors and genetic variants on two biological age measures: evidence from 94,443 Taiwan Biobank participants

2021 ◽  
Author(s):  
Wan-Yu Lin
Keyword(s):  
Genetic Variants ◽  
Genome Wide Association Study ◽  
Lifestyle Factors ◽  
Biological Age ◽  
Biological Aging ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Genome Wide ◽  
A Genome ◽  
The Uk

Abstract Background Biological age (BA) can be estimated by phenotypes and is useful for predicting lifespan and healthspan. Levine et al. proposed a PhenoAge and a BioAge to measure BA. Although there have been studies investigating the genetic predisposition to BA acceleration in Europeans, little has been known regarding this topic in Asians. Methods I here estimated PhenoAgeAccel (age-adjusted PhenoAge) and BioAgeAccel (age-adjusted BioAge) of 94,443 Taiwan Biobank (TWB) participants, wherein 25,460 TWB1 subjects formed a discovery cohort and 68,983 TWB2 individuals constructed a replication cohort. Lifestyle factors and genetic variants associated with PhenoAgeAccel and BioAgeAccel were investigated through regression analysis and a genome-wide association study (GWAS). Results A unit (kg/m 2) increase of BMI was associated with a 0.177-year PhenoAgeAccel (95% C.I. = 0.163~0.191, p = 6.0×) and 0.171-year BioAgeAccel (95% C.I. = 0.165~0.177, p = 0). Smokers on average had a 1.134-year PhenoAgeAccel (95% C.I. = 0.966~1.303, p = 1.3×) compared with non-smokers. Drinkers on average had a 0.640-year PhenoAgeAccel (95% C.I. = 0.433~0.847, p = 1.3×) and 0.193-year BioAgeAccel (95% C.I. = 0.107~0.279, p = 1.1×) relative to non-drinkers. A total of 11 and 4 single-nucleotide polymorphisms (SNPs) were associated with PhenoAgeAccel and BioAgeAccel (p&lt;5× in both TWB1 and TWB2), respectively. Conclusions A PhenoAgeAccel-associated SNP (rs1260326 in GCKR) and two BioAgeAccel-associated SNPs (rs7412 in APOE; rs16998073 near FGF5) were consistent with the finding from the UK Biobank. The lifestyle analysis shows that prevention from obesity, cigarette smoking, and alcohol consumption is associated with a slower rate of biological aging.

scholarly journals Genetic Variants Correlate With Better Processing Speed

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 163-164
Author(s):  
Anastasia Gurinovich ◽  
Kaare Christensen ◽  
Marianne Nygaard ◽  
Jonas Mengel-From ◽  
Stacy Andersen ◽  
...  
Keyword(s):  
Processing Speed ◽  
Genetic Variants ◽  
Cognitive Aging ◽  
Genome Wide Association Study ◽  
Brain Aging ◽  
P Value ◽  
Digit Symbol Substitution Test ◽  
Genome Wide ◽  
Common Genetic Variants ◽  
A Genome

Abstract Some cognitive abilities, such as vocabulary, are resilient to brain aging, while others such as conceptual reasoning, memory, and processing speed, decline with age and their rate of decline is genetically regulated. Despite the strong genetic heritability of processing speed assessed by the digit symbol substitution test (DSST), previous studies have failed to identify robust common genetic variants associated with this test. The Long Life Family Study (LLFS) includes long lived individuals and their family members who maintain good DSST scores as they age and who may carry variants associated with better DSST. We therefore conducted a genome-wide association study (GWAS) of DSST in LLFS using ~15M genetic variants imputed to the HRC panel of 64,940 haplotypes with 39,635,008 sites and replicated the findings using genetic data imputed to the 1000 Genomes phase 3 reference panel combining two Danish cohorts: the Middle Aged Danish Twins and the Longitudinal Study of Aging Danish Twins. The GWAS in LLFS discovered 20 rare genetic variants reaching genome-wide significance (p-value &lt; 5x10-8), including 18 variants associated with better processing speed with large effect size. The genetic associations of rs7623455, rs9821776, rs9821587, rs78704059 in chromosome 3 were replicated in the combined Danish cohort. These genetic variants tagged two hormone receptor related genes, THRB and RARB, both related to cognitive aging. Further gene-based tests in LLFS confirmed that these two genes have protective variants associated with better processing speed.

scholarly journals A genome-wide association study finds genetic variants associated with neck or shoulder pain in UK Biobank

2020 ◽  
Vol 29 (8) ◽  
pp. 1396-1404 ◽  
Author(s):  
Weihua Meng ◽  
Brian W Chan ◽  
Cameron Harris ◽  
Maxim B Freidin ◽  
Harry L Hebert ◽  
...  
Keyword(s):  
Association Study ◽  
Shoulder Pain ◽  
Genetic Variants ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Uk Biobank ◽  
Genome Wide ◽  
A Genome ◽  
Significant Locus ◽  
The Uk

Abstract Background Common types of musculoskeletal conditions include pain in the neck and shoulder areas. This study seeks to identify the genetic variants associated with neck or shoulder pain based on a genome-wide association approach using 203 309 subjects from the UK Biobank cohort and look for replication evidence from the Generation Scotland: Scottish Family Health Study (GS:SFHS) and TwinsUK. Methods A genome-wide association study was performed adjusting for age, sex, BMI and nine population principal components. Significant and independent genetic variants were then sent to GS:SFHS and TwinsUK for replication. Results We identified three genetic loci that were associated with neck or shoulder pain in the UK Biobank samples. The most significant locus was in an intergenic region in chromosome 17, rs12453010, having P = 1.66 × 10−11. The second most significant locus was located in the FOXP2 gene in chromosome 7 with P = 2.38 × 10−10 for rs34291892. The third locus was located in the LINC01572 gene in chromosome 16 with P = 4.50 × 10−8 for rs62053992. In the replication stage, among four significant and independent genetic variants, rs2049604 in the FOXP2 gene and rs62053992 in the LINC01572 gene were weakly replicated in GS:SFHS (P = 0.0240 and P = 0.0202, respectively). Conclusions We have identified three loci associated with neck or shoulder pain in the UK Biobank cohort, two of which were weakly supported in a replication cohort. Further evidence is needed to confirm their roles in neck or shoulder pain.

scholarly journals Genome-wide association study of skin and soft tissue infection susceptibility

2020 ◽  
Author(s):  
Tormod Rogne ◽  
Kristin V Liyanarachi ◽  
Humaira Rasheed ◽  
Laurent F Thomas ◽  
Helene M Flatby ◽  
...  
Keyword(s):  
Gene Expression ◽  
Soft Tissue ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Genome Wide Association ◽  
P Value ◽  
Uk Biobank ◽  
Genome Wide ◽  
Monocytes And Macrophages ◽  
The Uk

Background: Skin and soft tissue infections (SSTIs) are common worldwide, but little is known about the genetic susceptibility and the causal effect of cardiometabolic risk factors. We therefore conducted the first genome-wide association study (GWAS) of SSTIs, with downstream analyses including Mendelian randomization analyses. Methods: The GWAS was conducted using the UK Biobank as discovery cohort, with 6,107 cases and 399,239 controls, and the Trondelag Health Study (HUNT) as replication cohort with 1,657 cases and 67,522 controls. Cases and controls were those who had or had not been hospitalized with an SSTI diagnosis, respectively. Findings: One locus, lead single-nucleotide polymorphism rs3749748 in LINC01184/SLC12A2, was associated with SSTIs in the UK Biobank (odds ratio [OR] 1.19, p-value = 7.6e-16) and replicated in HUNT (OR 1.15, p-value = 6.3e-4). Meta-analysis confirmed the lead variant (OR 1.18, p-value = 4.4e-18), as well as suggested two additional loci close to genome-wide significance (rs2007361 in PSMA1, OR 0.91, p-value = 5.1e-8; and rs78625038 in GAN, OR 1.86, p-value = 5.9e-8). Gene-based association tests identified four genes linked to SSTIs: SLC12A2, PSMA1, GAN, and IL6R. The minor allele of rs3749748 reduced the gene expression of SLC12A2 primarily in monocytes and macrophages. Mendelian randomization analyses showed that increasing body mass index and lifetime smoking habits increased risk of SSTIs. Interpretation: LINC0118/SLC12A2 was robustly associated with SSTI incidence and may exert its effect through reduced gene expression in monocytes and macrophages. Reducing tobacco smoking, overweight and obesity in the population may reduce the incidence of SSTIs.

scholarly journals Genome-wide association study of breakfast skipping links clock regulation with food timing

2019 ◽  
Vol 110 (2) ◽  
pp. 473-484 ◽  
Author(s):  
Hassan S Dashti ◽  
Jordi Merino ◽  
Jacqueline M Lane ◽  
Yanwei Song ◽  
Caren E Smith ◽  
...  
Keyword(s):  
Association Study ◽  
Genetic Variants ◽  
Statistical Power ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Uk Biobank ◽  
Breakfast Cereal ◽  
Breakfast Skipping ◽  
Genome Wide ◽  
The Uk

ABSTRACT Background Little is known about the contribution of genetic variation to food timing, and breakfast has been determined to exhibit the most heritable meal timing. As breakfast timing and skipping are not routinely measured in large cohort studies, alternative approaches include analyses of correlated traits. Objectives The aim of this study was to elucidate breakfast skipping genetic variants through a proxy-phenotype genome-wide association study (GWAS) for breakfast cereal skipping, a commonly assessed correlated trait. Methods We leveraged the statistical power of the UK Biobank (n = 193,860) to identify genetic variants related to breakfast cereal skipping as a proxy-phenotype for breakfast skipping and applied several in silico approaches to investigate mechanistic functions and links to traits/diseases. Next, we attempted validation of our approach in smaller breakfast skipping GWAS from the TwinUK (n = 2,006) and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium (n = 11,963). Results In the UK Biobank, we identified 6 independent GWAS variants, including those implicated for caffeine (ARID3B/CYP1A1), carbohydrate metabolism (FGF21), schizophrenia (ZNF804A), and encoding enzymes important for N6-methyladenosine RNA transmethylation (METTL4, YWHAB, and YTHDF3), which regulates the pace of the circadian clock. Expression of identified genes was enriched in the cerebellum. Genome-wide correlation analyses indicated positive correlations with anthropometric traits. Through Mendelian randomization (MR), we observed causal links between genetically determined breakfast skipping and higher body mass index, more depressive symptoms, and smoking. In bidirectional MR, we demonstrated a causal link between being an evening person and skipping breakfast, but not vice versa. We observed association of our signals in an independent breakfast skipping GWAS in another British cohort (P = 0.032), TwinUK, but not in a meta-analysis of non-British cohorts from the CHARGE consortium (P = 0.095). Conclusions Our proxy-phenotype GWAS identified 6 genetic variants for breakfast skipping, linking clock regulation with food timing and suggesting a possible beneficial role of regular breakfast intake as part of a healthy lifestyle.

scholarly journals Genetic variants are identified to increase risk of COVID-19 related mortality from UK Biobank data

2021 ◽  
Vol 15 (1) ◽  
Author(s):  
Jianchang Hu ◽  
Cai Li ◽  
Shiying Wang ◽  
Ting Li ◽  
Heping Zhang
Keyword(s):  
Genetic Variants ◽  
Genetic Factors ◽  
Genome Wide Association Study ◽  
Individual Risk ◽  
Uk Biobank ◽  
Risk Of Death ◽  
Genome Wide ◽  
A Genome ◽  
Increased Risk ◽  
The Uk

Abstract Background The severity of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is highly heterogeneous. Studies have reported that males and some ethnic groups are at increased risk of death from COVID-19, which implies that individual risk of death might be influenced by host genetic factors. Methods In this project, we consider the mortality as the trait of interest and perform a genome-wide association study (GWAS) of data for 1778 infected cases (445 deaths, 25.03%) distributed by the UK Biobank. Traditional GWAS fails to identify any genome-wide significant genetic variants from this dataset. To enhance the power of GWAS and account for possible multi-loci interactions, we adopt the concept of super variant for the detection of genetic factors. A discovery-validation procedure is used for verifying the potential associations. Results We find 8 super variants that are consistently identified across multiple replications as susceptibility loci for COVID-19 mortality. The identified risk factors on chromosomes 2, 6, 7, 8, 10, 16, and 17 contain genetic variants and genes related to cilia dysfunctions (DNAH7 and CLUAP1), cardiovascular diseases (DES and SPEG), thromboembolic disease (STXBP5), mitochondrial dysfunctions (TOMM7), and innate immune system (WSB1). It is noteworthy that DNAH7 has been reported recently as the most downregulated gene after infecting human bronchial epithelial cells with SARS-CoV-2. Conclusions Eight genetic variants are identified to significantly increase the risk of COVID-19 mortality among the patients with white British ancestry. These findings may provide timely clues and potential directions for better understanding the molecular pathogenesis of COVID-19 and the genetic basis of heterogeneous susceptibility, with potential impact on new therapeutic options.

scholarly journals A genome-wide association study finds genetic variants associated with neck or shoulder pain in UK Biobank

2020 ◽  
Author(s):  
Weihua Meng ◽  
Brian W Chan ◽  
Cameron Harris ◽  
Maxim B Freidin ◽  
Harry L Hebert ◽  
...  
Keyword(s):  
Association Study ◽  
Shoulder Pain ◽  
Genetic Variants ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Chromosome 17 ◽  
Uk Biobank ◽  
Genome Wide ◽  
A Genome ◽  
The Uk

ABSTRACTBackgroundCommon types of musculoskeletal conditions include pain in the neck and shoulder areas. This study seeks to identify the genetic variants associated with neck or shoulder pain based on a genome-wide association approach using 203,309 subjects from the UK Biobank cohort and look for replication evidence from the Generation Scotland: Scottish Family Health Study (GS:SFHS) and TwinsUK.MethodsCases in the UK Biobank were determined by a question which asked the participants if they had experienced pain in the neck or shoulder in the previous month influencing daily activities. Controls were the UK Biobank participants who reported no pain anywhere in the last month. A genome-wide association study was performed adjusting for age, sex, BMI and 9 population principal components. Significant and independent genetic variants were then sent to GS:SFHS and TwinsUK for replication.ResultsWe identified 3 genetic loci that were associated with neck or shoulder pain in the UK Biobank samples. The most significant locus was in an intergenic region in chromosome 17, rs12453010, having P = 1.66 × 10-11. The second most significant locus was located in the FOXP2 gene in chromosome 7 with P = 2.38 × 10-10 for rs34291892. The third locus was located in the LINC01572 gene in chromosome 16 with P = 4.50 × 10-8 for rs62053992. In the replication stage, among 4 significant and independent genetic variants, rs2049604 in the FOXP2 gene and rs62053992 in the LINC01572 gene were weakly replicated in GS:SFHS (P = 0.0240 and P = 0.0202, respectively). None of the single nucleotide polymorphisms (SNPs) were replicated in the TwinsUK cohort (P > 0.05).ConclusionsWe have identified 3 loci associated with neck or shoulder pain in the UK Biobank cohort, two of which were weakly supported in a replication cohort. Further evidence is needed to confirm their roles in neck or shoulder pain.SignificanceThis is the first genome-wide association study on neck or shoulder pain. We have identified 3 genetic loci (an intergenic region in chromosome 17, the FOXP2 gene in chromosome 7, and the LINC01572 gene in chromosome 16) that are associated with neck or shoulder pain using the UK Biobank cohort, among which the FOXP2 gene and the LINC01572 gene were weakly replicated by the Generation Scotland: Scottish Family Health Study (P < 0.05). The SNP heritability was 0.11, indicating neck or shoulder pain is a heritable trait. The tissue expression analysis suggested that neck or shoulder pain was related to multiple brain tissues, indicating the involvement of neuron function. The results will inform further research in the characterisation of the mechanisms of neck or shoulder pain.

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