Allelic expression imbalance at high-density lipoprotein cholesterol locus MMAB-MVK.
Genome-wide association studies (GWAS) have identified numerous loci associated with various complex traits for which the underlying susceptibility gene(s) remain unknown. In a GWAS for high-density lipoprotein-cholesterol (HDL-C) level, one strongly associated locus contains at least two biologically compelling candidates, methylmalonic aciduria cblB type (MMAB) and mevalonate kinase (MVK). To detect evidence of cis-acting regulation at this locus, we measured relative allelic expression of transcribed SNPs in five genes using human hepatocyte samples heterozygous for the transcribed SNP. If an HDL-C-associated SNP allele differentially regulates mRNA level in cis, samples heterozygous both for a transcribed SNP and an HDL-C-associated SNP should display allelic expression imbalance (AEI) of the transcribed SNP. We designed statistical tests to detect AEI in a comprehensive set of linkage disequilibrium (LD) scenarios between the transcribed SNP and an HDL-C-associated SNP (rs7298565) in phase unknown samples. We observed significant AEI of 22% in MMAB (P = 1.4 x 10(-13), transcribed SNP rs11067231), and the allele associated with lower HDL-C level was associated with greater MMAB transcript level. The same rs7298565 allele was also associated with higher MMAB mRNA level (P = 0.0081) and higher MMAB protein level (P = 0.0020). In contrast, MVK, UBE3B, KCTD10 and ACACB did not show significant AEI (P > or = 0.05). These data suggest MMAB is the most likely gene influencing HDL-C levels at this locus and demonstrate that measuring AEI at loci containing more than one candidate gene can prioritize genes for functional studies.
Fogarty
Marie P
MP
Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA.
Xiao
Rui
R
Prokunina-Olsson
Ludmila
L
Scott
Laura J
LJ
Mohlke
Karen L
KL
D019883:Alkyl and Aryl Transferases / Q000235:genetics*; D000483:Alleles; D022981:Allelic Imbalance / Q000235:genetics*; D008076:Cholesterol, HDL / Q000235:genetics*; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic; D056426:Genetic Loci / Q000235:genetics*; D022781:Hepatocytes / Q000201:enzymology; D006801:Humans; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D008076:Cholesterol, HDL; D012333:RNA, Messenger; D019883:Alkyl and Aryl Transferases; C019920:cob(I)alamin adenosyltransferase; D017853:Phosphotransferases (Alcohol Group Acceptor); C021796:mevalonate kinase