Mega-analysis of 31,396 individuals from 6 countries uncovers strong gene-environment interaction for human fertility

Fc, Tropf; Rm, Verweij; Pj, van der Most; Stulp, Gert; Bakshi, Andrew; Da, Briley; Robinson, Matthew R.; Numan, Aisha Ismaila; Esko, Tõnu; Metspalu, Andres; Se, Medland; Mh, Ng; Snieder, Harold; Sh, Lee; Mc, Mills

doi:10.1101/049163

Cited by 12 publications

(11 citation statements)

References 58 publications

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“…Of note, consistent heritability estimates across different levels of the stratifying variable do not completely eliminate the potential existence of GxE interactions. Specifically, recent studies have identified genetic heterogeneity in human traits such as BMI and fertility [62,63], indicating that the genetic architecture of a trait may be different across environments (i.e., the genetic correlation of a trait in different environments may be significantly smaller than 1) even if the overall heritability estimates are similar. Dissection of common and unique environmental influences and their interactive effects with genetics on different complex traits, and the shared and unique genetic effects across environments are important future directions to explore.…”

Section: Discussionmentioning

confidence: 99%

Phenome-wide Heritability Analysis of the UK Biobank

Chen

Neale

et al. 2016

Preprint

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Heritability estimation provides important information about the relative contribution of genetic and environmental factors to phenotypic variation, and provides an upper bound for the utility of genetic risk prediction models. Recent technological and statistical advances have enabled the estimation of additive heritability attributable to common genetic variants (SNP heritability) across a broad phenotypic spectrum. Here, we present a computationally and memory efficient heritability estimation method that can handle large sample sizes, and report the SNP heritability for 551 complex traits derived from the interim data release (152,736 subjects) of the large-scale, population-based UK Biobank, comprising both quantitative phenotypes and disease codes. We demonstrate that common genetic variation contributes to a broad array of quantitative traits and human diseases in the UK population, and identify phenotypes whose heritability is moderated by age (e.g., a majority of physical measures including height and body mass index), sex (e.g., blood pressure related traits) and socioeconomic status (education). Our study represents the first comprehensive phenomewide heritability analysis in the UK Biobank, and underscores the importance of considering population characteristics in interpreting heritability. Author summaryHeritability of a trait refers to the proportion of phenotypic variation that is due to genetic variation among individuals. It provides important information about the genetic basis of complex traits and indicates whether a phenotype is an appropriate target for more specific statistical and molecular genetic analyses. Recent studies have leveraged the increasingly ubiquitous genome-wide data and documented the heritability attributable to common genetic variation captured by genotyping microarrays for a wide range of human traits. However, heritability is not a fixed property of a phenotype and can vary with population- specific differences in the genetic background and environmental variation. Here, using a computationally and memory efficient heritability estimation method, we report the heritability for a large number of traits derived from the large-scale, population-based UK Biobank, and, for the first time, demonstrate the moderating effect of three major demographic variables (age, sex and socioeconomic status) on heritability estimates derived from genomewide common genetic variation. Our study represents the first comprehensive heritability analysis across the phenotypic spectrum in the UK Biobank.

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Section: Discussionmentioning

confidence: 99%

Phenome-wide Heritability Analysis of the UK Biobank

Chen

Neale

et al. 2016

Preprint

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“…Next, we explored whether different genetic markers influence Neuroticism in different environments by testing for Gene × Environment interactions in a combined data set, using the cohort of origin as a proxy for the different environments (cf. Tropf et al, ).…”

Section: The Biological and Genetic Basis Of Neuroticismmentioning

confidence: 99%

SNP‐Based Heritability Estimates of Common and Specific Variance in Self‐ and Informant‐Reported Neuroticism Scales

Realo

Most

Allïk

et al. 2017

Journal of Personality

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“…Specifically, the G allele of rs2523393 was associated with longer intervals to pregnancy and lower expression of the HLA-F in mid-secretory phase (receptive) endometrium, whereas the A allele was associated with shorter intervals to pregnancy and higher HLA-F expression. The median time to pregnancy, for example, was 2.3, 2.6, and 4.9 months among women with the AA, GA, and GG genotypes, respectively [1][2][3]6 .…”

Section: Introductionmentioning

confidence: 99%

“…Female reproductive traits such as fertility, fecundity, and fecundability are heritable in humans 1,2 , however, identifying the genetic bases for these traits has been challenging [1][2][3] . We previously performed an integrated expression quantitative trait locus (eQTL) mapping and association study to identify eQTLs in mid-secretory endometrium that influence pregnancy outcomes 1,2,[4][5][6] .…”

Section: Introductionmentioning

confidence: 99%

An ancient fecundability-associated polymorphism creates a new GATA2 binding site in a distal enhancer ofHLA-F

Mika

DeMayo³

et al. 2018

Preprint

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Variation in female reproductive traits such as fertility, fecundity, and fecundability are heritable in humans, but identifying and functionally characterizing genetic variants associated with these traits has been challenging. Here we explore the functional significance and evolutionary history of a G/A polymorphism of SNP rs2523393, which we have previously shown is an eQTL for the HLA-F gene and significantly associated with fecundability (time to pregnancy). We replicated the association between rs2523393 genotype and HLA-F expression using GTEx data and demonstrate that HLA-F is up-regulated in the endometrium during the window of implantation and by progesterone in decidual stromal cells. Next, we show that the rs2523393 A allele creates a new GATA2 binding site in a progesterone responsive distal enhancer that loops to the HLA-F promoter. Remarkably, we found that the A allele is derived in the human lineage, that G/A polymorphism arose before the divergence of modern and archaic humans, and is segregating at intermediate to high frequencies across human populations. Remarkably, the derived A is also has been identified in a GWAS as a risk allele for multiple sclerosis. These data suggests that the polymorphism is maintained by antagonistic pleiotropy and a reproduction-health tradeoff in human evolution.

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Mega-analysis of 31,396 individuals from 6 countries uncovers strong gene-environment interaction for human fertility

Cited by 12 publications

References 58 publications

Phenome-wide Heritability Analysis of the UK Biobank

Phenome-wide Heritability Analysis of the UK Biobank

SNP‐Based Heritability Estimates of Common and Specific Variance in Self‐ and Informant‐Reported Neuroticism Scales

An ancient fecundability-associated polymorphism creates a new GATA2 binding site in a distal enhancer ofHLA-F

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