An investigation of obesity susceptibility genes in Northern Han Chinese by targeted resequencing

Our earlier genome-wide linkage study of body mass index (BMI) showed strong signals from 7q36.3 and 8q21.13. This case-control study set to investigate 2 genomic regions which may harbor variants contributed to development of obesity. We employed targeted resequencing technology to detect single nucleotide polymorphisms (SNPs) in 7q36.3 and 8q21.13 from 16 individuals with obesity. These were compared with 504 East Asians in the 1000 Genomes Project as a reference panel. Linkage disequilibrium (LD) block analysis was performed for the significant SNPs located near the same gene. Genes involved in statistically significant loci were then subject to gene set enrichment analysis (GSEA). The 16 individuals aged between 30 and 60 years with BMI= 33.25 +/- 2.22kg/m(2). A total of 12,131 genetic variants across all of samples were found. After correcting for multiple testing, 65 SNPs from 25 nearest genes (INSIG1, FABP5, PTPRN2, VIPR2, WDR60, SHH, UBE3C, LMBR1, PAG1, IMPA1, CHMP4, SNX16, BLACE, EN2, CNPY1, LOC100506302, RBM33, LOC389602, LOC285889, LINC01006, NOM1, DNAJB6, LOC101927914, ESYT2, LINC00689) were associated with obesity at significant level q-value <= 0.05. LD block analysis showed there were 10 pairs of loci with D'>= 0.8 and r(2)>= 0.8. GSEA further identified 2 major related gene sets, involving lipid raft and lipid metabolic process, with FDR values <0.12 and <0.4, respectively. Our data are the first documentation of genetic variants in 7q36.3 and 8q21.13 associated with obesity using target capture sequencing and Northern Han Chinese samples. Additional replication and functional studies are merited to validate our findings. Abbreviations: AF = allele frequency, Alt. = alteration, BLACE = B-cell acute lymphoblastic leukemia expressed, BMI = body mass index, BWA = Burrows-Wheeler aligner, CHMP4 = charged multivesicular body protein 4B, Chr. = chromosome, CNPY1 = canopy FGF signaling regulator 1, DNA = deoxyribonucleic acid, DNAJB6 = DnaJ heat shock protein family (Hsp40) Member B6, EN2 = engrailed homeobox 2, ESYT2 = extended synaptotagmin protein 2, FABP5 = fatty acid binding protein 5, FDR = false discovery rate, GATK = Genome Analysis Toolkit, GO = genetic ontology, GSEA = gene set enrichment analysis, GWAS = genomewide association studies, IMPA1 = inositol monophosphatase 1, INSIG1 = insulin induced gene 1, LD = linkage disequilibrium, LINC00689 = long intergenic nonprotein coding RNA 689, LINC01006 = long intergenic nonprotein coding RNA 1006, LMBR1 = limb development membrane protein 1, LOC100506302 = uncharacterized LOC100506302, LOC101927914 = uncharacterized LOC101927914, LOC285889 = uncharacterized LOC285889, LOC389602 = uncharacterized LOC389602, NGSQC = Next Generation Sequencing Quality Control, NOM1 = nucleolar protein with MIF4G domain 1, PAG1 = phosphoprotein membrane anchor with glycosphingolipid microdomains 1, PCR = polymerase chain reaction, PTPRN2 = protein tyrosine phosphatase, receptor type N2, RBM33 = RNA binding motif protein 33, Ref. = reference, SHH = Sonic Hedgehog, SNP = single nucleotide polymorphisms, SNX16 = sorting Nexin 16, UBE3C = ubiquitin protein ligase E3C, VIP = vasoactive intestinal polypeptide, VIPR2 = vasoactive intestinal peptide receptor 2, WDR60 = WD repeat domain 60.