: Return 3301

Notes

Genotype-by-environment interaction (GEI) is a fundamental component in understanding complex trait variation. However, it remains challenging to identify genetic variants with GEI effects in humans largely because of the small effect sizes and the difficulty of monitoring environmental fluctuations. Here, we demonstrate that GEI can be inferred from genetic variants associated with phenotypic variability in a large sample without the need of measuring environmental factors. We performed a genome-wide variance quantitative trait locus (vQTL) analysis of ~5.6 million variants on 348,501 unrelated individuals of European ancestry for 13 quantitative traits in the UK Biobank and identified 75 significant vQTLs with P < 2.0e-9 for 9 traits, especially for those related to obesity. Direct GEI analysis with five environmental factors showed that the vQTLs were strongly enriched with GEI effects. Our results indicate pervasive GEI effects for obesity-related traits and demonstrate the detection of GEI without environmental data.

Application 12505

Dissecting the genetic basis of relationships between early-life and later-life events

Differences among individuals in distinct changes in their physiology as they age lead to differences in their susceptibility to negative later-life outcomes, and ultimately to differences in lifespan. This proposal aims to test whether genetic differences among individuals influence changes in cognition and physiological function in later life, to identify the genomic regions and biochemical pathways associated with these changes, and to test for genetic associations between early-life reproduction and later-life outcomes. This is crucial to understanding and predicting transitions across different human life stages. Understanding the genetic basis of relationships between early-life phenotypes, reproductive events, and later-life outcomes is of considerable research and public health interest. This proposal will identify new genetic relationships among physiological and cognitive functions, identify genomic regions of age-specific effect, estimate genetic relationships among life stages, and test the effects of genetic homozygosity in the genome in humans across life. It will lead to a better understanding of the genetic factors and biochemical pathways underlying cognitive and physiological decline in people as they age. Establishing robust genetic links between early and later-life health outcomes is challenging as (i) it usually requires studying people across their lives, and, when using families, (ii) relationships are confounded by other factors, such as shared environment between relatives. A novel design for studying the genetics of ageing will be used, so that even when different traits are measured on different individuals, the genetic basis of changes across life can be studied unbiased of shared environment. This enables an assessment of the genomic basis of multiple later-life phenotypes across different ages, testing theories for the genetics of ageing. For sufficient power to accurately estimate genetic relationships between characters, we require access to the full cohort. Even though individuals in the UKBiobank sample are measured across different ages, we can utilize the estimated genetic relationships among them to ask whether the genetic basis of characters is consistent across later life. We can then assess whether variation in genetic effects across life alters genetic relationships among characters throughout life (i.e., do the impacts of early-life on cognitive or physiological function only become apparent in individuals over 65). This requires data on all individuals recorded across all ages.

Lead investigator:	Professor Peter Visscher
Lead institution:	University of Queensland

10 related Returns

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3583	12505	A unified framework for association and prediction from vertex-wise grey-matter structure	22 Jun 2021
3201	12505	Association Between Population Density and Genetic Risk for Schizophrenia	11 Mar 2021
1831	12505	Detection and quantification of inbreeding depression for complex traits from SNP data	26 Nov 2019
2904	12505	Dissection of genetic variation and evidence for pleiotropy in male pattern baldness	30 Nov 2020
3365	12505	Extreme inbreeding in a European ancestry sample from the contemporary UK population	22 Apr 2021
3393	12505	Genome-wide association study identifies 143 loci associated with 25 hydroxyvitamin D concentration	29 Apr 2021
3630	12505	Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies	9 Jul 2021
3255	12505	Improved polygenic prediction by Bayesian multiple regression on summary statistics	26 Mar 2021
3447	12505	The effect of X-linked dosage compensation on complex trait variation	25 May 2021
3672	12505	Theoretical and empirical quantification of the accuracy of polygenic scores in ancestry divergent populations	27 Jul 2021

1 Publication

Pub ID	Title	Author(s)	Year	Journal
3302	Genotype-by-environment interactions inferred from genetic effects on phenotypic variability in the UK Biobank	Wang H et al.	2019	Sci Adv

Application:	12505, Dissecting the genetic basis of relationships between early-life and later-life events
Title:	Genotype-by-environment interactions inferred from genetic effects on phenotypic variability in the UK Biobank
Size:	230440 B
Archived:	9 Apr 2021
Stability:	Complete
Personal:	No individual-level data