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.
Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA.
Marie P
MP
Fogarty
Rui
R
Xiao
Ludmila
L
Prokunina-Olsson
Laura J
LJ
Scott
Karen L
KL
Mohlke
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