Pathogen exposure misclassification can bias association signals in GWAS of infectious diseases when using population-based common controls DOI Creative Commons
Dylan Duchen, Candelaria Vergara, Chloe L. Thio

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: July 17, 2022

ABSTRACT Genome-wide association studies (GWAS) have been performed to identify host genetic factors for a range of phenotypes, including infectious diseases. The use population-based common controls from biobanks and extensive consortiums is valuable resource increase sample sizes in the identification associated loci with minimal additional expense. Non-differential misclassification outcome has reported when are not well-characterized, which often attenuates true effect size. However, diseases comparison cases regardless pathogen exposure can also result selection bias. Through simulated comparisons exposed controls, we demonstrate that accounting biased estimates spurious genome-wide significant signals. Further, observed be distorted depending upon strength between locus prevalence exposure. We used real data example hepatitis C virus (HCV) consortium comparing HCV spontaneous clearance persistent infection both well characterized UK Biobank. find known clearance-associated potentially clearance-associations. These findings suggest choice especially important or outcomes conditional environmental exposures.

Language: Английский

Principles and methods for transferring polygenic risk scores across global populations DOI
Linda Kachuri, Nilanjan Chatterjee, Jibril Hirbo

et al.

Nature Reviews Genetics, Journal Year: 2023, Volume and Issue: 25(1), P. 8 - 25

Published: Aug. 24, 2023

Language: Английский

Citations

140
The expanding diagnostic toolbox for rare genetic diseases DOI
Kristin D. Kernohan, Kym M. Boycott

Nature Reviews Genetics, Journal Year: 2024, Volume and Issue: 25(6), P. 401 - 415

Published: Jan. 18, 2024

Language: Английский

Citations

30
Clinical, technical, and environmental biases influencing equitable access to clinical genetics/genomics testing: A points to consider statement of the American College of Medical Genetics and Genomics (ACMG) DOI Creative Commons
Dena R. Matalon, Cinthya Zepeda‐Mendoza, Mahmoud Aarabi

et al.

Genetics in Medicine, Journal Year: 2023, Volume and Issue: 25(6), P. 100812 - 100812

Published: April 14, 2023

Language: Английский

Citations

26
Assessing the contribution of rare protein-coding germline variants to prostate cancer risk and severity in 37,184 cases DOI Creative Commons
Jonathan Mitchell, Niedzica Camacho, Patrick R. Shea

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 19, 2025

Abstract To assess the contribution of rare coding germline genetic variants to prostate cancer risk and severity, we perform here a meta-analysis 37,184 cases 331,329 male controls from five cohorts with whole exome or genome sequencing data, one cohort imputed array data. At gene level, our case-control collapsing analysis confirms associations between damaging in four genes increased risk: SAMHD1 , BRCA2 ATM at study-wide significance level ( P < 1×10 −8 ), CHEK2 suggestive threshold 2.6×10 −6 ). Our case-only analysis, reveals that AOX1 are associated more aggressive disease (OR = 2.60 [1.75–3.83], 1.35×10 as well confirming role determining severity. single-variant study missense variant TERT is substantially reduced 0.13 [0.07–0.25], 4.67×10 −10 non-synonymous further three ANO7 SPDL1 AR ) HOXB13 BIK Altogether, this work provides deeper insights into architecture biological basis potential implications for clinical prediction therapeutic strategies.

Language: Английский

Citations

1
Recent advances and challenges of rare variant association analysis in the biobank sequencing era DOI Creative Commons
Wenan Chen, Brandon J. Coombes, Nicholas B. Larson

et al.

Frontiers in Genetics, Journal Year: 2022, Volume and Issue: 13

Published: Oct. 6, 2022

Causal variants for rare genetic diseases are often in the general population. Rare may also contribute to common complex traits and can have much larger per-allele effect sizes than variants, although power detect these associations be limited. Sequencing costs steadily declined with technological advancements, making it feasible adopt whole-exome whole-genome profiling large biobank-scale sample sizes. These amounts of sequencing data provide both opportunities challenges rare-variant association analysis. Herein, we review basic concepts analysis methods, current state-of-the-art methods utilizing variant annotations or external controls improve statistical power, particular facing such as accounting population structure, extremely unbalanced case-control design. We recent advances familial more phenotypes survival data. Finally, discuss other potential directions further methodology investigation.

Language: Английский

Citations

29
Public platform with 39,472 exome control samples enables association studies without genotype sharing DOI Creative Commons
Mykyta Artomov, Alexander Loboda, Maxim N. Artyomov

et al.

Nature Genetics, Journal Year: 2024, Volume and Issue: 56(2), P. 327 - 335

Published: Jan. 10, 2024

Abstract Acquiring a sufficiently powered cohort of control samples matched to case sample can be time-consuming or, in some cases, impossible. Accordingly, an ability leverage genetic data from that were already collected elsewhere could dramatically improve power association studies. Sharing pose significant challenges, since most human are subject strict sharing regulations. Here, using the properties singular value decomposition and subsampling algorithm, we developed method allowing selection best-matching controls external pool compliant with personal protection eliminating need for genotype sharing. We provide access library 39,472 exome sequencing at http://dnascore.net enabling studies cohorts lacking subjects. Using this approach, sets selected online prespecified matching accuracy, ensuring well-calibrated analysis both rare common variants.

Language: Английский

Citations

8
Increase in power by obtaining 10 or more controls per case when type-1 error is small in large-scale association studies DOI Creative Commons
Hormuzd A. Katki, Sonja I. Berndt, Mitchell J. Machiela

et al.

BMC Medical Research Methodology, Journal Year: 2023, Volume and Issue: 23(1)

Published: June 29, 2023

The rule of thumb that there is little gain in statistical power by obtaining more than 4 controls per case, based on type-1 error α = 0.05. However, association studies evaluate thousands or millions associations use smaller and may have access to plentiful controls. We investigate gains, reductions p-values, when increasing well beyond for small α.We calculate the power, median expected p-value, minimum detectable odds-ratio (OR), as a function number controls/case, decreases.As decreases, at each ratio increase larger For between 10-6 10-9 (typical associations), from case 10-50 increases power. example, study with 0.2 (α 5 × 10-8) 1 control/case has 0.65 but 10 controls/case 0.78, 50 0.84. situations where provides 0.9 (at α), p-value can decrease orders-of-magnitude below α. Increasing reduces OR toward null 20.9%, an additional 9.7%, result which applies regardless hence also "regular" 0.05 epidemiology.At α, versus recruiting controls/cases reduce 1-2 orders magnitude, meaningfully OR. These benefits cases increases, although amount benefit depends exposure frequencies true Provided are comparable cases, our findings suggest greater sharing large-scale studies.

Language: Английский

Citations

15
Rare and common genetic variants underlying the risk of Hirschsprung’s disease DOI
Jun Xiao,

Chenzhao Feng,

Tianqi Zhu

et al.

Human Molecular Genetics, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 16, 2025

Abstract Hirschsprung’s disease (HSCR) is a congenital enteric neuropathic disorder characterized by high heritability (&gt;80%) and polygenic inheritance (&gt;20 genes). The previous genome-wide association studies (GWAS) identified several common variants associated with HSCR demonstrated increased predictive performance for risk in Europeans using genetic score, there remains notable gap knowledge regarding Chinese populations. We conducted whole exome sequencing case cohort Chinese. By the controls (505 from 1KG EAS 10 588 ChinaMAP), we GWAS gene-based rare variants. further validated genes replicated samples vitro vivo experiments. one novel gene PLK5 suggested 45 putative based test. variant at RET PLK5, constructed score that could identify individuals very HSCR. Compared patients zero or allele three variants, was 36.61 times higher six alleles. In addition, delineated landscape encompasses 57 genes, which explains 88.5% 54.5% of European, respectively. summary, this study improved understanding architecture provided prediction approach

Language: Английский

Citations

0
Characterizing substructure via mixture modeling in large-scale genetic summary statistics DOI Creative Commons
Hayley R Stoneman,

Adelle Price,

Nikole Scribner Trout

et al.

The American Journal of Human Genetics, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

Citations

0
Divergent biological pathways linking short and long sleep durations to mental and physical health DOI

Yuzhu Li,

Weikang Gong, Barbara J. Sahakian

et al.

Nature Mental Health, Journal Year: 2025, Volume and Issue: unknown

Published: March 3, 2025

Language: Английский

Citations

0