Leveraging DNA methylation quantitative trait loci to characterize the relationship between methylomic variation, gene expression and complex traits

Hannon, Eilís; Gorrie-Stone, T.J.; Smart, Melissa; Burrage, Joe; Hughes, Amanda; Bao, Yanchun; Schalkwyk, Leonard C.; Mill, Jonathan

doi:10.1101/297176

Cited by 13 publications

(24 citation statements)

References 53 publications

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“…SNPs and 43,337 DNA methylation sites. The whole blood mQTL dataset was generated using DNAm and SNP data from 2,082 individuals 78 and included 30,432,023 cis mQTLs between 4,030,902 SNPs and 167,854 DNA methylation sites. mQTLs reaching the significance threshold P ≤ × 10 -10 were taken forward for SMR analysis as described by Hannon and colleagues 78 .…”

Section: Summary-based Mendelian Randomizationmentioning

confidence: 99%

“…The prefrontal cortex mQTL dataset was generated using DNA methylation and SNP data from 522 individuals from the Brains for Dementia Research cohort and included 4,623,966 cis mQTLs (distance between QTL SNP and DNAm site ≤ 500 kb) between 1,744,102 SNPs and 43,337 DNA methylation sites. The whole blood mQTL dataset was generated using DNAm and SNP data from 2,082 individuals 78 and included 30,432,023 cis mQTLs between 4,030,902 SNPs and 167,854 DNA methylation sites. mQTLs reaching the significance threshold P ≤ × 10 -10 were taken forward for SMR analysis as described by Hannon and colleagues 78 .…”

Section: Summary-based Mendelian Randomizationmentioning

confidence: 99%

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Common and rare variant association analyses in Amyotrophic Lateral Sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

Rheenen

Spek

Bakker

et al. 2021

Preprint

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a life-time risk of 1 in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry GWAS in ALS including 29,612 ALS patients and 122,656 controls which identified 15 risk loci in ALS. When combined with 8,953 whole-genome sequenced individuals (6,538 ALS patients, 2,415 controls) and the largest cortex-derived eQTL dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, repeat expansions or regulatory effects. ALS associated risk loci were shared with multiple traits within the neurodegenerative spectrum, but with distinct enrichment patterns across brain regions and cell-types. Of the environmental and life-style risk factors obtained from literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. All ALS associated signals combined reveal a role for perturbations in vesicle mediated transport and autophagy, and provide evidence for cell-autonomous disease initiation in glutamatergic neurons.

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Section: Summary-based Mendelian Randomizationmentioning

confidence: 99%

Section: Summary-based Mendelian Randomizationmentioning

confidence: 99%

Common and rare variant association analyses in Amyotrophic Lateral Sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

Rheenen

Spek

Bakker

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…The prefrontal cortex mQTL dataset was generated using DNA methylation and SNP data from 522 individuals from the Brains for Dementia Research cohort 22 and included 4,623,966 cis mQTLs (distance between QTL SNP and DNAm site ≤ 500 kb) between 1,744,102 SNPs and 43,337 DNA methylation sites. The whole blood mQTL dataset was generated using DNAm and SNP data from 2,082 individuals 78 and included 30,432,023 cis mQTLs between 4,030,902 SNPs and 167,854 DNA methylation sites. mQTLs reaching the significance threshold P ≤ 1 × 10 -10 were taken forward for SMR analysis as described by Hannon and colleagues 78 .…”

Section: Summary-based Mendelian Randomizationmentioning

confidence: 99%

Common and rare variant association analyses in Amyotrophic Lateral Sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

Rheenen

Spek

Bakker

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a life-time risk of 1 in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry GWAS in ALS including 29,612 ALS patients and 122,656 controls which identified 15 risk loci in ALS. When combined with 8,953 whole-genome sequenced individuals (6,538 ALS patients, 2,415 controls) and the largest cortex-derived eQTL dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, repeat expansions or regulatory effects. ALS associated risk loci were shared with multiple traits within the neurodegenerative spectrum, but with distinct enrichment patterns across brain regions and cell-types. Across environmental and life-style risk factors obtained from literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. All ALS associated signals combined reveal a role for perturbations in vesicle mediated transport and autophagy, and provide evidence for cell-autonomous disease initiation in glutamatergic neurons.

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“…Next, we harmonized the retrieved data by converting them to SMR 20 or GSMR 21 format for downstream analyses. We obtained GWAS summary statistics for SNPs that influence the human blood proteome (pQTLs) from Sun et al 22 GWAS summary statistics for SNPs that influence transcriptome (eQTLs) were from Võsa et al 23 and GWAS summary statistics for SNPs that influence DNA methylation (mQTLs) were derived from two studies 19,24 . These studies are independent with reference to study participants and were conducted using blood samples.…”

Section: Data Sourcesmentioning

confidence: 99%

Convergence of biomarkers and risk factor trait loci of coronary artery disease at 3p21.31 and HLA region

Nikpay

McPherson

2021

npj Genom. Med.

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Here we seek to identify molecular biomarkers that mediate the effect of risk factors on coronary artery disease (CAD). We perform a SNP-based multiomics data analysis to find biomarkers (probes) causally associated with the risk of CAD within known genomic loci for its risk factors. We identify 78 biomarkers, the majority (64%) of which are methylation probes. We detect the convergence of several CNS and lifestyle trait loci and their biomarkers at the 3p21.31 and human leukocyte antigen (HLA) regions. The 3p21.31 locus was the most populated region in the convergence of biomarkers and risk factors. In this region, we noted as the BSN gene becomes methylated the level of stomatin (STOM) in blood increases and this contributes to higher risk of CAD. In the HLA locus, we identify several methylation biomarkers associated with various CAD risk factors. SNPs in the CFB gene display a trans-regulatory impact on the GRIA4 protein level. A methylation site upstream of the APOE gene is associated with a higher protein level of S100A13 which in turn leads to higher LDL-C and greater CAD risk. We find UHRF1BP1 and ILRUN mediate the effect of obesity on CAD whereas methylation sites within NOS3 and CKM mediate the effect of their associated-risk factors on CAD. This study provides further insight into the biology of CAD and identifies a list of biomarkers that mediate the impact of risk factors on CAD. A SNP-based initiative can unite data from various fields of omics into a single network of knowledge.

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Leveraging DNA methylation quantitative trait loci to characterize the relationship between methylomic variation, gene expression and complex traits

Cited by 13 publications

References 53 publications

Common and rare variant association analyses in Amyotrophic Lateral Sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

Common and rare variant association analyses in Amyotrophic Lateral Sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

Common and rare variant association analyses in Amyotrophic Lateral Sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

Convergence of biomarkers and risk factor trait loci of coronary artery disease at 3p21.31 and HLA region

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