scholarly journals Rare, low frequency and common coding variants in CHRNA5 and their contribution to nicotine dependence in European and African Americans

2015 ◽  
Vol 21 (5) ◽  
pp. 601-607 ◽  
Author(s):  
E Olfson ◽  
N L Saccone ◽  
E O Johnson ◽  
L-S Chen ◽  
R Culverhouse ◽  
...  
Keyword(s):  
African Americans ◽  
Nicotine Dependence ◽  
Low Frequency ◽  
Common Coding ◽  
Coding Variants

scholarly journals Low-frequency variant functional architectures reveal strength of negative selection across coding and non-coding annotations

2018 ◽  
Author(s):  
Steven Gazal ◽  
Po-Ru Loh ◽  
Hilary K. Finucane ◽  
Andrea Ganna ◽  
Armin Schoech ◽  
...  
Keyword(s):  
Negative Selection ◽  
Rare Variants ◽  
Association Studies ◽  
Low Frequency ◽  
Common Variant ◽  
Cell Type ◽  
Functional Annotations ◽  
Common Coding ◽  
Cell Type Specific ◽  
Coding Variants

AbstractCommon variant heritability is known to be concentrated in variants within cell-type-specific non-coding functional annotations, with a limited role for common coding variants. However, little is known about the functional distribution of low-frequency variant heritability. Here, we partitioned the heritability of both low-frequency (0.5% ≤ MAF < 5%) and common (MAF ≥ 5%) variants in 40 UK Biobank traits (average N = 363K) across a broad set of coding and non-coding functional annotations, employing an extension of stratified LD score regression to low-frequency variants that produces robust results in simulations. We determined that non-synonymous coding variants explain 17±1% of low-frequency variant heritability versus only 2.1±0.2% of common variant heritability , and that regions conserved in primates explain nearly half of (43±2%). Other annotations previously linked to negative selection, including non-synonymous variants with high PolyPhen-2 scores, non-synonymous variants in genes under strong selection, and low-LD variants, were also significantly more enriched for as compared to . Cell-type-specific non-coding annotations that were significantly enriched for of corresponding traits tended to be similarly enriched for for most traits, but more enriched for brain-related annotations and traits. For example, H3K4me3 marks in brain DPFC explain 57±12% of vs. 12±2% of for neuroticism, implicating the action of negative selection on low-frequency variants affecting gene regulation in the brain. Forward simulations confirmed that the ratio of low-frequency variant enrichment vs. common variant enrichment primarily depends on the mean selection coefficient of causal variants in the annotation, and can be used to predict the effect size variance of causal rare variants (MAF < 0.5%) in the annotation, informing their prioritization in whole-genome sequencing studies. Our results provide a deeper understanding of low-frequency variant functional architectures and guidelines for the design of association studies targeting functional classes of low-frequency and rare variants.

scholarly journals Assessing the contribution of rare-to-common protein-coding variants to circulating metabolic biomarker levels via 412,394 UK Biobank exome sequences

2021 ◽  
Author(s):  
Abhishek Nag ◽  
Lawrence Middleton ◽  
Ryan S Dhindsa ◽  
Dimitrios Vitsios ◽  
Eleanor M Wigmore ◽  
...  
Keyword(s):  
Gene Networks ◽  
Rare Variants ◽  
Association Studies ◽  
Low Frequency ◽  
Genome Wide Association Studies ◽  
Uk Biobank ◽  
Protein Coding ◽  
The Uk ◽  
Metabolic Biomarkers ◽  
Coding Variants

Genome-wide association studies have established the contribution of common and low frequency variants to metabolic biomarkers in the UK Biobank (UKB); however, the role of rare variants remains to be assessed systematically. We evaluated rare coding variants for 198 metabolic biomarkers, including metabolites assayed by Nightingale Health, using exome sequencing in participants from four genetically diverse ancestries in the UKB (N=412,394). Gene-level collapsing analysis, that evaluated a range of genetic architectures, identified a total of 1,303 significant relationships between genes and metabolic biomarkers (p<1x10-8), encompassing 207 distinct genes. These include associations between rare non-synonymous variants in GIGYF1 and glucose and lipid biomarkers, SYT7 and creatinine, and others, which may provide insights into novel disease biology. Comparing to a previous microarray-based genotyping study in the same cohort, we observed that 40% of gene-biomarker relationships identified in the collapsing analysis were novel. Finally, we applied Gene-SCOUT, a novel tool that utilises the gene-biomarker association statistics from the collapsing analysis to identify genes having similar biomarker fingerprints and thus expand our understanding of gene networks.

Low-frequency coding variants associated with body-mass-index impact the success of bariatric surgery

2021 ◽  
Author(s):  
Darlène Antoine ◽  
Rosa-Maria Guéant-Rodriguez ◽  
Jean-Claude Chèvre ◽  
Sébastien Hergalant ◽  
Tanmay Sharma ◽  
...  
Keyword(s):  
Bariatric Surgery ◽  
Body Mass Index ◽  
Morbid Obesity ◽  
General Population ◽  
Body Mass ◽  
Intervention Program ◽  
Low Frequency ◽  
European Ancestry ◽  
Frequency Coding ◽  
Coding Variants

Abstract Context A recent study identified 14 low-frequency coding variants associated with body-mass-index (BMI) in 718,734 individuals predominantly of European ancestry. Objective and design The 14 low-frequency coding variants were genotyped or sequenced in 342 French adults with severe/morbid obesity and 574 French adult controls from the general population. We built risk and protective genetic scores (GS) based on 6 BMI-increasing and 5 BMI-decreasing low-frequency coding variants that were polymorphic in our study. We investigated the association of the two GS with i) the risk of severe/morbid obesity, ii) BMI variation before weight-loss intervention, iii) BMI change in response to an 18-month lifestyle/behavioral intervention program, and iv) BMI change up to 24 months after bariatric surgery. Results While the risk GS was not associated with severe/morbid obesity status, BMI-decreasing low-frequency coding variants were significantly less frequent in patients with severe/morbid obesity than in French adults from the general population. Neither the risk nor the protective GS was associated with BMI before intervention in patients with severe/morbid obesity, nor did they impact BMI change in response to a lifestyle/behavioral modification program. The protective GS was associated with a greater BMI decrease following bariatric surgery. The risk and protective GS were associated with a higher and lower risk of BMI regain after bariatric surgery. Conclusion Our data indicate that in populations of European descent, low-frequency coding variants associated with BMI in the general population also impact the outcomes of bariatric surgery in patients with severe/morbid obesity.

scholarly journals Role of Rare and Low-Frequency Variants in Gene-Alcohol Interactions on Plasma Lipid Levels

2020 ◽  
Vol 13 (4) ◽  
Author(s):  
Zhe Wang ◽  
Han Chen ◽  
Traci M. Bartz ◽  
Lawrence F. Bielak ◽  
Daniel I. Chasman ◽  
...  
Keyword(s):  
Alcohol Consumption ◽  
Plasma Lipid ◽  
Low Frequency ◽  
Environment Interaction ◽  
Lipid Levels ◽  
Protein Coding ◽  
Gene Environment Interaction ◽  
Gene Environment ◽  
Coding Variants

Background: Alcohol intake influences plasma lipid levels, and such effects may be moderated by genetic variants. We aimed to characterize the role of aggregated rare and low-frequency protein-coding variants in gene by alcohol consumption interactions associated with fasting plasma lipid levels. Methods: In the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, fasting plasma triglycerides and high- and low-density lipoprotein cholesterol were measured in 34 153 individuals with European ancestry from 5 discovery studies and 32 277 individuals from 6 replication studies. Rare and low-frequency functional protein-coding variants (minor allele frequency, ≤5%) measured by an exome array were aggregated by genes and evaluated by a gene-environment interaction test and a joint test of genetic main and gene-environment interaction effects. Two dichotomous self-reported alcohol consumption variables, current drinker, defined as any recurrent drinking behavior, and regular drinker, defined as the subset of current drinkers who consume at least 2 drinks per week, were considered. Results: We discovered and replicated 21 gene-lipid associations at 13 known lipid loci through the joint test. Eight loci ( PCSK9 , LPA , LPL , LIPG , ANGPTL4 , APOB , APOC3 , and CD300LG ) remained significant after conditioning on the common index single-nucleotide polymorphism identified by previous genome-wide association studies, suggesting an independent role for rare and low-frequency variants at these loci. One significant gene-alcohol interaction on triglycerides in a novel locus was significantly discovered ( P =6.65×10 −6 for the interaction test) and replicated at nominal significance level ( P =0.013) in SMC5 . Conclusions: In conclusion, this study applied new gene-based statistical approaches and suggested that rare and low-frequency genetic variants interacted with alcohol consumption on lipid levels.

scholarly journals Common coding variants in the HLA-DQB1 region confer susceptibility to age-related macular degeneration

2016 ◽  
Vol 24 (7) ◽  
pp. 1049-1055 ◽  
Author(s):  
Eric Jorgenson ◽  
Ronald B Melles ◽  
Thomas J Hoffmann ◽  
Xiaoming Jia ◽  
Lori C Sakoda ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Age Related Macular Degeneration ◽  
Common Coding ◽  
Age Related ◽  
Coding Variants

scholarly journals Population-scale analysis of common and rare genetic variation associated with hearing loss in adults

2021 ◽  
Author(s):  
Kavita Praveen ◽  
Lee Dobbyn ◽  
Lauren Gurski ◽  
Ariane H. Ayer ◽  
Jeffrey Staples ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Exome Sequencing ◽  
Large Scale ◽  
Meta Analysis ◽  
Adult Population ◽  
Loss Of Function ◽  
Common Coding ◽  
A Genome ◽  
Increased Risk ◽  
Coding Variants

ABSTRACTUnderstanding the genetic underpinnings of disabling hearing loss, which affects ∼466 million people worldwide, can provide avenues for new therapeutic target development. We performed a genome-wide association meta-analysis of hearing loss with 125,749 cases and 469,497 controls across five cohorts, including UK Biobank, Geisinger DiscovEHR, the Malmö Diet and Cancer Study, Mount Sinai’s BioMe Personalized Medicine Cohort, and FinnGen. We identified 53 loci affecting hearing loss risk, 15 of which are novel, including common coding variants in COL9A3 and TMPRSS3. Through exome-sequencing of 108,415 cases and 329,581 controls from the same cohorts, we identified hearing loss associations with burden of rare coding variants in FSCN2 (odds ratio [OR] = 1.14, P = 1.9 × 10−15) and burden of predicted loss-of-function variants in KLHDC7B (OR = 2.14, P = 5.2 × 10−30). We also observed single-variant and gene-burden associations with 11 genes known to cause Mendelian forms of hearing loss, including an increased risk in heterozygous carriers of mutations in the autosomal recessive hearing loss genes GJB2 (Gly12fs; OR = 1.21, P = 4.2 × 10−11) and SLC26A5 (gene burden; OR = 1.96, P = 2.8 × 10−17). Our results suggest that loss of KLHDC7B function increases risk for hearing loss, and show that Mendelian hearing loss genes contribute to the burden of hearing loss in the adult population, suggesting a shared etiology between common and rare forms of hearing loss. This work illustrates the potential of large-scale exome sequencing to elucidate the genetic architecture of common traits in which risk is modulated by both common and rare variation.

scholarly journals Impact of rare and common genetic variants on diabetes diagnosis by hemoglobin A1c in multi-ancestry cohorts: The Trans-Omics for Precision Medicine Program

2019 ◽  
Author(s):  
Chloé Sarnowski ◽  
Aaron Leong ◽  
Laura M Raffield ◽  
Peitao Wu ◽  
Paul S de Vries ◽  
...  
Keyword(s):  
African Americans ◽  
Precision Medicine ◽  
Hemoglobin A1c ◽  
Sequence Data ◽  
African Ancestry ◽  
Low Frequency ◽  
Diabetes Diagnosis ◽  
Common Genetic Variants ◽  
Patients With Diabetes ◽  
The Uk

AbstractHemoglobin A1c (HbA1c) is widely used to diagnose diabetes and assess glycemic control in patients with diabetes. However, nonglycemic determinants, including genetic variation, may influence how accurately HbA1c reflects underlying glycemia. Analyzing the NHLBI Trans-Omics for Precision Medicine (TOPMed) sequence data in 10,338 individuals from five studies and four ancestries (6,158 Europeans, 3,123 African-Americans, 650 Hispanics and 407 East Asians), we confirmed five regions associated with HbA1c (GCK in Europeans and African-Americans, HK1 in Europeans and Hispanics, FN3K/FN3KRP in Europeans and G6PD in African-Americans and Hispanics) and discovered a new African-ancestry specific low-frequency variant (rs1039215 in HBG2/HBE1, minor allele frequency (MAF)=0.03). The most associated G6PD variant (p.Val98Met, rs1050828-T, MAF=12% in African-Americans, MAF=2% in Hispanics) lowered HbA1c (−0.88% in hemizygous males, −0.34% in heterozygous females) and explained 23% of HbA1c variance in African-Americans and 4% in Hispanics. Additionally, we identified a rare distinct G6PD coding variant (rs76723693 - p.Leu353Pro, MAF=0.5%; −0.98% in hemizygous males, −0.46% in heterozygous females) and detected significant association with HbA1c when aggregating rare missense variants in G6PD. We observed similar magnitude and direction of effects for rs1039215 (HBG2) and rs76723693 (G6PD) in the two largest TOPMed African-American cohorts and replicated the rs76723693 association in the UK Biobank African-ancestry participants. These variants in G6PD and HBG2 were monomorphic in the European and Asian samples. African or Hispanic ancestry individuals carrying G6PD variants may be underdiagnosed for diabetes when screened with HbA1c. Thus, assessment of these variants should be considered for incorporation into precision medicine approaches for diabetes diagnosis.

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