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Discovery and prioritization of variants and genes for kidney function in >1.2 million individuals.

ABSTRACT: Genes underneath signals from genome-wide association studies (GWAS) for kidney function are promising targets for functional studies, but prioritizing variants and genes is challenging. By GWAS meta-analysis for creatinine-based estimated glomerular filtration rate (eGFR) from the Chronic Kidney Disease Genetics Consortium and UK Biobank (n = 1,201,909), we expand the number of eGFRcrea loci (424 loci, 201 novel; 9.8% eGFRcrea variance explained by 634 independent signal variants). Our increased sample size in fine-mapping (n = 1,004,040, European) more than doubles the number of signals with resolved fine-mapping (99% credible sets down to 1 variant for 44 signals, ≤5 variants for 138 signals). Cystatin-based eGFR and/or blood urea nitrogen association support 348 loci (n = 460,826 and 852,678, respectively). Our customizable tool for Gene PrioritiSation reveals 23 compelling genes including mechanistic insights and enables navigation through genes and variants likely relevant for kidney function in human to help select targets for experimental follow-up.

SUBMITTER: Stanzick KJ

PROVIDER: S-EPMC8285412 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Discovery and prioritization of variants and genes for kidney function in >1.2 million individuals.

Stanzick Kira J KJ Li Yong Y Schlosser Pascal P Gorski Mathias M Wuttke Matthias M Thomas Laurent F LF Rasheed Humaira H Rowan Bryce X BX Graham Sarah E SE Vanderweff Brett R BR Patil Snehal B SB Robinson-Cohen Cassiane C Gaziano John M JM O'Donnell Christopher J CJ Willer Cristen J CJ Hallan Stein S Åsvold Bjørn Olav BO Gessner Andre A Hung Adriana M AM Pattaro Cristian C Köttgen Anna A Stark Klaus J KJ Heid Iris M IM Winkler Thomas W TW

Nature communications 20210716 1

Genes underneath signals from genome-wide association studies (GWAS) for kidney function are promising targets for functional studies, but prioritizing variants and genes is challenging. By GWAS meta-analysis for creatinine-based estimated glomerular filtration rate (eGFR) from the Chronic Kidney Disease Genetics Consortium and UK Biobank (n = 1,201,909), we expand the number of eGFRcrea loci (424 loci, 201 novel; 9.8% eGFRcrea variance explained by 634 independent signal variants). Our increase ...[more]

PMID: 34272381

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Project description:BackgroundChildhood adversity such as poverty, loss of a parent, and dysfunctional family dynamics may be associated with exposure to environmental and behavioral hazards, interfere with normal biological functions, and affect cancer care and outcomes. To explore this hypothesis, we assessed the cancer burden among young men and women exposed to adversity during childhood.MethodsWe undertook a population-based study using Danish nationwide register data on childhood adversity and cancer outcomes. Children who were alive and resident in Denmark until their 16th birthday were followed into young adulthood (16-38 years). Group-based multi-trajectory modelling was used to categorize individuals into five distinct groups: low adversity, early material deprivation, persistent material deprivation, loss/threat of loss, and high adversity. We assessed the association with overall cancer incidence, mortality, and five-year case fatality; and cancer specific outcomes for the four most common cancers in this age group in sex-stratified survival analyses.Findings1,281,334 individuals born between Jan 1, 1980, and Dec 31, 2001, were followed up until Dec 31, 2018, capturing 8229 incident cancer cases and 662 cancer deaths. Compared to low adversity, women who experienced persistent material deprivation carried a slightly lower risk of overall cancer (hazard ratio (HR) 0.90; 95% CI 0.82; 0.99), particularly due to malignant melanoma and brain and central nervous system cancers, while women who experienced high adversity carried a higher risk of breast cancer (HR 1.71; 95% CI 1.09; 2.70) and cervical cancer incidence (HR 1.82; 95% CI 1.18; 2.83). While there was no clear association between childhood adversity and cancer incidence in men, those men who had experienced persistent material deprivation (HR 1.72; 95% CI 1.29; 2.31) or high adversity (HR 2.27; 95% CI 1.38; 3.72) carried a disproportionate burden of cancer mortality during adolescence or young adulthood compared to men in the low adversity group.InterpretationChildhood adversity is associated with a lower risk of some subtypes of cancer and a higher risk of others, particular in women. Persistent deprivation and adversity are also associated with a higher risk of adverse cancer outcomes for men. These findings may relate to a combination of biological susceptibility, health behaviors and treatment-related factors.FundingNone.

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Discovery and prioritization of variants and genes for kidney function in >1.2 million individuals.

Publications

Discovery and prioritization of variants and genes for kidney function in >1.2 million individuals.

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Dataset Information

Discovery and prioritization of variants and genes for kidney function in >1.2 million individuals.

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Discovery and prioritization of variants and genes for kidney function in &gt;1.2 million individuals.

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OmicsDI is part of the ELIXIR infrastructure

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Discovery and prioritization of variants and genes for kidney function in >1.2 million individuals.