A Genome-Wide mQTL Analysis in Human Adipose Tissue Identifies Genetic Variants Associated with DNA Methylation, Gene Expression and Metabolic Traits.
Little is known about the extent to which interactions between genetics and epigenetics may affect the risk of complex metabolic diseases and/or their intermediary phenotypes. We performed a genome-wide DNA methylation quantitative trait locus (mQTL) analysis in human adipose tissue of 119 men, where 592,794 single nucleotide polymorphisms (SNPs) were related to DNA methylation of 477,891 CpG sites, covering 99% of RefSeq genes. SNPs in significant mQTLs were further related to gene expression in adipose tissue and obesity related traits. We found 101,911 SNP-CpG pairs (mQTLs) in cis and 5,342 SNP-CpG pairs in trans showing significant associations between genotype and DNA methylation in adipose tissue after correction for multiple testing, where cis is defined as distance less than 500 kb between a SNP and CpG site. These mQTLs include reported obesity, lipid and type 2 diabetes loci, e.g. ADCY3/POMC, APOA5, CETP, FADS2, GCKR, SORT1 and LEPR. Significant mQTLs were overrepresented in intergenic regions meanwhile underrepresented in promoter regions and CpG islands. We further identified 635 SNPs in significant cis-mQTLs associated with expression of 86 genes in adipose tissue including CHRNA5, G6PC2, GPX7, RPL27A, THNSL2 and ZFP57. SNPs in significant mQTLs were also associated with body mass index (BMI), lipid traits and glucose and insulin levels in our study cohort and public available consortia data. Importantly, the Causal Inference Test (CIT) demonstrates how genetic variants mediate their effects on metabolic traits (e.g. BMI, cholesterol, high-density lipoprotein (HDL), hemoglobin A1c (HbA1c) and homeostatic model assessment of insulin resistance (HOMA-IR)) via altered DNA methylation in human adipose tissue. This study identifies genome-wide interactions between genetic and epigenetic variation in both cis and trans positions influencing gene expression in adipose tissue and in vivo (dys)metabolic traits associated with the development of obesity and diabetes.
Department of Clinical Sciences, Epigenetics and Diabetes, Lund University Diabetes Centre, Clinical Research Centre, Malmö, Sweden.
Petr
P
Volkov
Department of Clinical Sciences, Epigenetics and Diabetes, Lund University Diabetes Centre, Clinical Research Centre, Malmö, Sweden.|Department of Endocrinology, Diabetes and Metabolism, Rigshospitalet, Copenhagen, Denmark.
Anders H
AH
Olsson
Department of Endocrinology, Diabetes and Metabolism, Rigshospitalet, Copenhagen, Denmark.
Linn
L
Gillberg
Department of Endocrinology, Diabetes and Metabolism, Rigshospitalet, Copenhagen, Denmark.
Sine W
SW
Jørgensen
Department of Endocrinology, Diabetes and Metabolism, Rigshospitalet, Copenhagen, Denmark.
Charlotte
C
Brøns
Department of Clinical Sciences, Vascular Diseases, Lund University, Malmö, Sweden.
Karl-Fredrik
KF
Eriksson
Department of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre, Clinical Research Centre, Malmö, Sweden.
Leif
L
Groop
The Lundberg Laboratory for Diabetes Research, Center of Excellence for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska University Hospital, University of Gothenburg, Gothenburg, Sweden.
Per-Anders
PA
Jansson
Department of Clinical Sciences, Epigenetics and Diabetes, Lund University Diabetes Centre, Clinical Research Centre, Malmö, Sweden.|Department of Endocrinology, Diabetes and Metabolism, Rigshospitalet, Copenhagen, Denmark.
Emma
E
Nilsson
Department of Clinical Sciences, Epigenetics and Diabetes, Lund University Diabetes Centre, Clinical Research Centre, Malmö, Sweden.
Tina
T
Rönn
Department of Endocrinology, Diabetes and Metabolism, Rigshospitalet, Copenhagen, Denmark.
Allan
A
Vaag
Department of Clinical Sciences, Epigenetics and Diabetes, Lund University Diabetes Centre, Clinical Research Centre, Malmö, Sweden.
Charlotte
C
Ling
D000273:Adipose Tissue / Q000378:metabolism*; D000328:Adult; D015992:Body Mass Index; D015331:Cohort Studies; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D005786:Gene Expression Regulation; D056726:Genetic Association Studies; D014644:Genetic Variation; D015894:Genome, Human; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D008297:Male; D009765:Obesity / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics*; D019655:Quantitative Trait, Heritable; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D012537:Scandinavian and Nordic Countries
D006442:Glycated Hemoglobin; D012333:RNA, Messenger