Abstract:Insights into individual differences in gene expression and its heritability (h 2) can help in understanding pathways from DNA to phenotype. We estimated the heritability of gene expression of 52,844 genes measured in whole blood in the largest twin RNA-Seq sample to date (1497 individuals including 459 monozygotic twin pairs and 150 dizygotic twin pairs) from classical twin modeling and identity-by-state-based approaches. We estimated for each gene h 2 total , composed of cisheritability (h 2 cis , the varian… Show more
“…Our findings are in line with previous studies reporting an influence of the common environment for a minority of the investigated metabolites, with average contributions of the common environment frequently lower even than the 0.25 we observed (Kettunen et al, 2012;Menni et al, 2013;Yet et al, 2016). The limited contribution of the common environment on metabolite levels is also consistent with observations for other molecular traits, such as expression (Ouwens et al, 2020;Wright et al, 2014) or methylation levels (van Dongen et al, 2016), which were measured in the same group of twin pairs as in this work. This is in stark contrast to a recent family-based study that reported substantial familial resemblance in metabolite levels to which common environment had the strongest contribution (Tremblay et al, 2019).…”
AbstractMetabolites are small molecules involved in cellular metabolism where they act as reaction substrates or products. The term ‘metabolomics’ refers to the comprehensive study of these molecules. The concentrations of metabolites in biological tissues are under genetic control, but this is limited by environmental factors such as diet. In adult mono- and dizygotic twin pairs, we estimated the contribution of genetic and shared environmental influences on metabolite levels by structural equation modeling and tested whether the familial resemblance for metabolite levels is mainly explained by genetic or by environmental factors that are shared by family members. Metabolites were measured across three platforms: two based on proton nuclear magnetic resonance techniques and one employing mass spectrometry. These three platforms comprised 237 single metabolic traits of several chemical classes. For the three platforms, metabolites were assessed in 1407, 1037 and 1116 twin pairs, respectively. We carried out power calculations to establish what percentage of shared environmental variance could be detected given these sample sizes. Our study did not find evidence for a systematic contribution of shared environment, defined as the influence of growing up together in the same household, on metabolites assessed in adulthood. Significant heritability was observed for nearly all 237 metabolites; significant contribution of the shared environment was limited to 6 metabolites. The top quartile of the heritability distribution was populated by 5 of the 11 investigated chemical classes. In this quartile, metabolites of the class lipoprotein were significantly overrepresented, whereas metabolites of classes glycerophospholipids and glycerolipids were significantly underrepresented.
“…Our findings are in line with previous studies reporting an influence of the common environment for a minority of the investigated metabolites, with average contributions of the common environment frequently lower even than the 0.25 we observed (Kettunen et al, 2012;Menni et al, 2013;Yet et al, 2016). The limited contribution of the common environment on metabolite levels is also consistent with observations for other molecular traits, such as expression (Ouwens et al, 2020;Wright et al, 2014) or methylation levels (van Dongen et al, 2016), which were measured in the same group of twin pairs as in this work. This is in stark contrast to a recent family-based study that reported substantial familial resemblance in metabolite levels to which common environment had the strongest contribution (Tremblay et al, 2019).…”
AbstractMetabolites are small molecules involved in cellular metabolism where they act as reaction substrates or products. The term ‘metabolomics’ refers to the comprehensive study of these molecules. The concentrations of metabolites in biological tissues are under genetic control, but this is limited by environmental factors such as diet. In adult mono- and dizygotic twin pairs, we estimated the contribution of genetic and shared environmental influences on metabolite levels by structural equation modeling and tested whether the familial resemblance for metabolite levels is mainly explained by genetic or by environmental factors that are shared by family members. Metabolites were measured across three platforms: two based on proton nuclear magnetic resonance techniques and one employing mass spectrometry. These three platforms comprised 237 single metabolic traits of several chemical classes. For the three platforms, metabolites were assessed in 1407, 1037 and 1116 twin pairs, respectively. We carried out power calculations to establish what percentage of shared environmental variance could be detected given these sample sizes. Our study did not find evidence for a systematic contribution of shared environment, defined as the influence of growing up together in the same household, on metabolites assessed in adulthood. Significant heritability was observed for nearly all 237 metabolites; significant contribution of the shared environment was limited to 6 metabolites. The top quartile of the heritability distribution was populated by 5 of the 11 investigated chemical classes. In this quartile, metabolites of the class lipoprotein were significantly overrepresented, whereas metabolites of classes glycerophospholipids and glycerolipids were significantly underrepresented.
“…The weak contribution of the cis-genetic background to gene expression in blood is in line with the findings reported in twin studies that estimated the mean heritability ( h 2 ) of blood gene expression ranging between 0.101 and 0.26 depending on the methodology used for gene expression analysis (microarray or RNAseq) 43 , 44 . The limited effect of GReX component on blood gene expression in MDD patients could in part reflect the fact that MDD is primarily a brain disease 2 , 3 as emerged from GWAS studies that consistently reported association of the disease with variants harbored in genes mainly expressed in the brain.…”
Major depressive disorder (MDD) is a common psychiatric disorder with a multifactorial aetiology determined by the interaction between genetic and environmental risk factors. Pieces of evidence indicate that inflammation and immune activation may contribute to the onset of MDD playing a role in the pathogenetic mechanism. To date, it is not known to which extent the association between MDD and inflammation is shaped by the genetic background or by the presence of environmental factors. To clarify this issue, we analyzed genotype and blood RNA profiles of 463 MDD cases and 459 controls (NIMH-Study 88/Site621) estimating the Genetic and Environmental Regulated eXpression component of gene expression (GReX and EReX respectively). Both components were tested for association with MDD. Many genes belonging to the α/β interferon signaling pathway showed an association between MDD and EReX, only two between MDD and GReX. Also other MDD differentially expressed genes were more influenced by the EReX than by GReX. These results suggest that impact of the genetic background on MDD blood gene expression alterations is much lower than the contribution of environmental factors and almost absent for the genes of the interferon pathway.
“… Figure 8—figure supplement 14. Distributions of (left) total SNP-based heritability of gene expression, or (right) fraction of expression SNP-based heritability driven by cis-effects ( Ouwens et al, 2020 ) for genes in the indicated core pathways, or for all other MsigDB genes not in a core pathway. Points indicate means, error bars indicate two standard deviations.…”
Genome-wide association studies (GWAS) have been used to study the genetic basis of a wide variety of complex diseases and other traits. We describe UK Biobank GWAS results for three molecular traits—urate, IGF-1, and testosterone—with better-understood biology than most other complex traits. We find that many of the most significant hits are readily interpretable. We observe huge enrichment of associations near genes involved in the relevant biosynthesis, transport, or signaling pathways. We show how GWAS data illuminate the biology of each trait, including differences in testosterone regulation between females and males. At the same time, even these molecular traits are highly polygenic, with many thousands of variants spread across the genome contributing to trait variance. In summary, for these three molecular traits we identify strong enrichment of signal in putative core gene sets, even while most of the SNP-based heritability is driven by a massively polygenic background.
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