Chinese Han Nationality Population Height And Body Mass Index Of Genome-wide Association Studies

Part One:Genome-wide association study of human height in Han ChineseBackground and objectiveHuman height is mainly determined by genetic factors with heritability estimates of80%. Insights into the genetic determination of height will provide a better understanding of human development and growth. Up to now, most genome-wide association studies (GWAS) of height were conducted in European populations. So we conduct a meta-analysis of GWAS for human height in Chinese Han population with replication to identify genetic underpinnings in Chinese.Subjects and methodsThis study included GWAS discovery studies of6534Han Chinese subjects from Beijing Atherosclerosis Study (BAS) and China Atherosclerosis Study (CAS). The BAS subjects were genotyped with the Affymetrix GeneChip(?) Human Mapping500K Array Set and CAS subjects were genotyped with the AxiomTM Genome-Wide CHB1Array. Top SNPs in loci that achieved genome-wide significance (P<5.0×10-8) or suggestive evidence (5.0×10-8<P<1.0×10-5) were replicated in the Genetic Epidemiology Network of Salt Sensitivity (GenSalt) study. The1881subjects of GenSalt study were genotyped using Affymetrix(?) Genome-Wide Human Array6.0.ResultsThrough meta-analysis of discovery studies, we identified two loci that reached the genome-wide significance level of P<5×10-8. These included one locus at CYP19A1(rs3751599, P=1.86×10-9) reported in populations of European descent and one unreported locus at ZNF638(rs12612930, P=1.07×10-8). We selected17top SNPs in17loci (P<1×10-5) from the discovery study for replication in the GenSalt study. Combined analysis of discovery and replication studies strengthened the original associations of the CYP19A1and ZNF638loci with height (rs3751599, P=4.80×10-10; rs12612930, P=2.02×10-10) in a total of8415subjects. We also observed another three loci reached genome-wide significance in combined analysis. rs11021504on11q21(MAML2, P=7.81×10-9) and rs11082671on18q21.1(C18orf12, P=1.87×10-8) were newly identified. Another locus on12q13.3(rs3816804, P=2.63×10-9) had been reported previously. Finally, we identified three novel loci (ZNF638, MAML2and C18orf12) and confirmed two loci (CS and CYP19A1) previously reported in European populations.We evaluated the associations of eight SNPs that achieved genome-wide significance in GWAS of other Asian populations in our discovery study. All these SNPs were in the same effect directions of previous studies and four showed nominal significance (P<0.05) including rs3791675(EFEMP1, P=4.32×10-4),rs7571816(DIS3L2, P=9.50×10-4), rs7678436(NCAPG-LCORL, P=5.52×10-4) and rs12338076(LHX3-QSOX2, P=3.42×10-2). We also investigated whether the height-associated SNPs identified by non-Asian GWAS were associated in our sample. We found35SNPs showed directionally consistent and nominally significant associations in the discovery study (P<0.05).ConclusionWe identified three novel loci reaching the genome-wide significance threshold (P<5×10-8) including ZNF638, MAML2and C18orf12. We also confirmed two loci previously reported in European populations including CS and CYP19A1. Our data suggest that both shared and unique genetic backgrounds of human height are present in different ancestry groups. Further studies are required to confirm associations of loci identified in this study across different populations and elucidate the underlying molecular mechanisms of growth in the future.Part Two:Genome-wide association study of body mass index in Han ChineseBackground and objectiveObesity is a global public health problem. Up to now, genome-wide association studies (GWAS) have identified more than fifty loci that influence body mass index (BMI) and obesity. Most of these loci were identified in samples of European origin, and only several of them were replicated in Asian populations. It implied that there might be substantial genetic differences for BMI among different populations. Therefore, we carried out this GWAS of BMI in Han Chinese with replication study to investigate the genetic basis of BMI.in Chinese.Subjects and methodsThis study included GWAS discovery studies of6534Han Chinese subjects from Beijing Atherosclerosis Study (BAS) and China Atherosclerosis Study (CAS). Subjects from BAS and CAS were genotyped with the Affymetrix GeneChip(?) Human Mapping500K Array Set and the AxiomTM Genome-Wide CHB1Array, respectively. Top SNPs in loci that achieved suggestive evidence (P<1.0×10-5) were replicated in the Genetic Epidemiology Network of Salt Sensitivity (GenSalt) study. The1881subjects of GenSalt study were genotyped using Affymetrix(?) Genome-Wide Human Array6.0.ResultsIn the meta-analysis of6534participants from discovery stage, seven loci showed suggestive association with P less than1×10-5. These included two previously reported BMI loci (FTO, rs17817712, P=3.21×10-6and MC4R, rs975918, P=9.80×10-6) and five new loci (CMTM7, rs347134, P=2.56×10-6; VEPH1, rs16827528, P=3.97×10-6; RPL18P9, rs12818806, P=2.98×10-6; GJA3, rs4769965, P=1.17×10-6and C14orf177, rs17097110, P=5.92×10-6). We selected tops SNPs of these seven loci for replication in the GenSalt study. Three SNPs showed nominal significance(P<0.05) in replication study including two SNPs on chromosome3(rs347134, CMTM7, P=3.39×10-2; rs16827528, VEPH1, P=3.47×10-3) and one SNP on chromosome18(rs975918, MC4R, P=2.79×10-2). In the combined analysis of discovery and replication studies with8415subjects, one locus (VEPH1, rsl6827528, P=4.85×10-8) on chromosome3reached genome-wide significance. Two loci previously reported did not reached genome-wide significance in the combined analysis (FTO, rs17817712, P=1.05×105; MC4R, rs975918, P=8.72×10-7).We evaluated whether the51BMI-related loci identified in previous studies were associated with BMI in our discovery study. Besides FTO and MC4R, another eight loci showed nominal association with BMI (P<0.05) including TMEM18, SEC16B, GNPDA2, PCSK1, CDKAL1, MTCH2, GP2and NPC1. For the other41loci, six were monomorphic in Chinese Han population and35did not show significant association with BMI (P>0.05). ConclusionIn this GWAS of BMI in Han Chinese, we newly identified one locus (VEPH1) associated with BMI and four loci (CMTM7, RPL18P9, GJA3and C14orf177) potentially associated with BMI. We also replicated10previously reported BMI loci including FTO, MC4R, TMEM18, SEC16B, GNPDA2, PCSK1, CDKAL1, MTCH2, GP2and NPC1, with P values ranging from4.42×10-2to8.72×10-7. New loci from this study need validation in studies of large sample sizes across different population. Fine mapping and functional studies may help to explain the genetic mechanism of these loci.