Biology subjects

McRae, A.

Publications and source records attributed to McRae, A..

3 recordsLinked to original sources

bioRxiv2017

Identification of 55,000 Replicated DNA Methylation QTL

DNA methylation plays an important role in the regulation of transcription. Genetic control of DNA methylation is a potential candidate for explaining the many identified SNP associations with disease that are not found in coding regions. We replicated 52,916 cis and 2,025 trans DNA methylation quantitative trait loci (mQTL) using methylation measured on Illumina HumanMethylation450 arrays in the Brisbane Systems Genetics Study (n=614 from 177 families) and the Lothian Birth Cohorts of 1921 and 1936 (combined n = 1366). The trans mQTL SNPs were found to be over-represented in 1Mbp subtelomeric regions, and on chromosomes 16 and 19. There was a significant increase in trans mQTL DNA methylation sites in upstream and 5 UTR regions. No association was observed between either the SNPs or DNA methylation sites of trans mQTL and telomere length. The genetic heritability of a number of complex traits and diseases was partitioned into components due to mQTL and the remainder of the genome. Significant enrichment was observed for height (p = 2.1x10-10), ulcerative colitis (p = 2x10-5), Crohns disease (p = 6x10-8) and coronary artery disease (p = 5.5x10-6) when compared to a random sample of SNPs with matched minor allele frequency, although this enrichment is explained by the genomic location of the mQTL SNPs.

genomics↗

bioRxiv2017

GWAS of epigenetic ageing rates in blood reveals a critical role for TERT

DNA methylation age is an accurate biomarker of chronological age and predicts lifespan, but its underlying molecular mechanisms are unknown. In this genome-wide association study of 9,907 individuals, we found gene variants mapping to five loci associated with intrinsic epigenetic age acceleration (IEAA) and gene variants in 3 loci associated extrinsic epigenetic age acceleration (EEAA). Mendelian randomization analysis suggested causal influences of menarche and menopause on IEAA and lipid levels on IEAA and EEAA. Variants associated with longer leukocyte telomere length (LTL) in the telomerase reverse transcriptase gene (TERT) locus at 5p15.33 confer higher IEAA (P<2.7x10-11). Causal modelling indicates TERT-specific and independent effects on LTL and IEAA. Experimental hTERT expression in primary human fibroblasts engenders a linear increase in DNA methylation age with cell population doubling number. Together, these findings indicate a critical role for hTERT in regulating the DNA methylation clock, in addition to its established role of compensating for cell replication-dependent telomere shortening.

genetics↗

bioRxiv2017

Widespread signatures of negative selection in the genetic architecture of human complex traits

Estimation of the joint distribution of effect size and minor allele frequency (MAF) for genetic variants is important for understanding the genetic basis of complex trait variation and can be used to detect signature of natural selection. We develop a Bayesian mixed linear model that simultaneously estimates SNP-based heritability, polygenicity (i.e. the proportion of SNPs with nonzero effects) and the relationship between effect size and MAF for complex traits in conventionally unrelated individuals using genome-wide SNP data. We apply the method to 28 complex traits in the UK Biobank data (N = 126,752), and show that on average across 28 traits, 6% of SNPs have nonzero effects, which in total explain 22% of phenotypic variance. We detect significant (p < 0.05/28 =1.8x10-3) signatures of natural selection for 23 out of 28 traits including reproductive, cardiovascular, and anthropometric traits, as well as educational attainment. We further apply the method to 27,869 gene expression traits (N = 1,748), and identify 30 genes that show significant (p < 2.3x10-6) evidence of natural selection. All the significant estimates of the relationship between effect size and MAF in either complex traits or gene expression traits are consistent with a model of negative selection, as confirmed by forward simulation. We conclude that natural selection acts pervasively on human complex traits shaping genetic variation in the form of negative selection.

genetics↗