中国汉族人群身高和体重指数的全基因组关联研究

发布时间：2018-01-01 16:06

本文关键词：中国汉族人群身高和体重指数的全基因组关联研究　出处：《北京协和医学院》2013年博士论文　论文类型：学位论文

【摘要】：第一部分中国汉族人群身高的全基因组关联研究背景和目的身高主要受遗传因素控制,其遗传度约为80%。研究身高的遗传机制将有助于深入理解人类生长发育过程。到目前为止,大部分身高的全基因组关联研究是在欧洲人群开展的。因此,我们在中国汉族人群中开展了这项全基因组关联研究并进行重复验证,来探讨中国汉族人群身高的遗传因素。研究对象和方法本研究的芯片阶段纳入了来自北京动脉粥样硬化研究和中国动脉粥样硬化研究的6534名研究对象。北京动脉粥样硬化研究和中国动脉粥样硬化研究分别使用Affymetrix的GeneChip(?)500K和AxiomTM全基因组CHB1阵列芯片进行基因分型。挑选芯片阶段达到全基因组显著性(P5.0×10-8)或潜在关联(5.0×10-8P1.O×10-5)的位点在盐敏感性遗传流行病学网络(GenSalt)研究中进行重复验证。GenSalt的1881名研究对象使用Affymetrix(?)6.0芯片进行基因分型。结果通过芯片阶段的meta分析,我们发现了两个位点达到全基因组显著水平。这两个位点分别是欧洲人群中已报道的CYP19A1位点(rs3751599, P=1.86×10-9)和从未报道过的ZNF638位点(rs12612930,P=1.07×10-8)。我们从芯片阶段选择了17个位点在GenSalt研究中进行了重复验证。将芯片阶段和重复验证阶段结果合并后,CYP19A1和ZNF638与身高的关联变得更为显著(rs3751599,P＝4.80×10-10；rs12612930,P=2.02x10-10)。除这两个位点外,还有其它3个位点达到了全基因组显著性。其中,11q21的MAML2(rs11021504,P=7.81×10-9)和18q21.1的C18orf12(rs11082671,P=1.87×10-8)为新发现的位点,12q13.3的CS(rs3816804,P=2.63×10-9)为已报道过的位点。因此,在将芯片阶段和重复验证阶段合并共计8415研究对象中,我们发现了三个新的身高位点(ZNF638、MAML2和C18orf12)并验证了两个已报道的位点(CS和CYP19A1)。我们分析了亚洲人群中已报道的8个身高位点在本研究芯片阶段的关联结果。所有8个位点在本研究中的效应方向均与以往亚洲人群研究报道的方向相同并且4个位点显示显著关联(P0.05)。这4个位点的SNP分别为rs3791675(EFEMP1,P=432×10-4), rs7571816(DIS3L2, P=9.50×10-4), rs7678436(NCAPG-LCORL, P=5.52×10-4)和rs12338076(LHX3-QSOX2,P=3.42×10-2)。同样,我们也评估了其他人群中报道的身高位点在本研究中与身高的关联情况,共有35个位点在本研究中提示有显著关联的证据(P0.05)。结论本研究在汉族人群中发现了三个新的身高相关位点,分别为ZNF638、MAML2和C18orfl2。此外还验证了两个以往报道的位点,分别为CS和CYP19A1。这些研究结果表明,身高的遗传机制在不同人种之间既有共同又有不同之处。应当开展进一步研究对这些位点在不同人群中进行验证并解释其潜在的生物学机制。第二部分中国汉族人群体重指数的全基因组关联研究背景和目的肥胖是全球重要的公共卫生问题。目前为止,全基因组关联研究已经发现50多个与肥胖和体重指数相关联的位点。这些位点大多是在欧洲人群中发现的,仅有部分在亚洲人群中得到验证。这提示体重指数这一复杂性状的遗传机制在不同种族之间有一定的差异,需要在不同种族中开展体重指数的全基因组关联研究并相互验证。因此,本研究在中国汉族人群中开展体重指数全基因组关联研究并在独立样本中进行重复验证,来探讨中国汉族人群体重指数的遗传因素。研究对象和方法本研究芯片阶段纳入的6534名研究对象分别来自北京动脉粥样硬化研究和中国动脉粥样硬化研究。北京动脉粥样硬化研究使用Affymetrix的GeneChip(？)500K,中国动脉粥样硬化研究使用AxiomTM全基因组CHB1阵列芯片进行全基因组基因分型。芯片阶段达到潜在关联(P1.0×10-5)的位点进入重复验证分析阶段。重复验证采用盐敏感性遗传流行病学网络(GenSalt)研究,1881名研究对象已使用Afymetrix(?)6.0芯片进行基因分型。结果通过对6534名研究对象的芯片阶段分析,我们发现7个位点的P值小于1×10-5。这7个位点包括两个已报道的体重指数相关位点分别为FTO(rs17817712,P=3.21×10-6)和MC4R (rs975918, P=9.80×10-6),还有5个新位点CMTM7(rs347134, P=2.56×10-6)、VEPH1(rs16827528, P=3.97×10-6)、 RPL18P9(rs12818806,P=2.98×10-6)、GJA3(rs4769965,P=1.17R10-6)和C14orf177(rs17097110, P=5.92×10-6)。我们将从芯片阶段筛选出的这7个位点关联信号最强的SNP在GenSalt研究中进行了重复验证,其中3个在重复验证阶段提示有显著关联证据(P0.05)。这3个SNP分别位于3号染色体的CMTM7(rs347134, P=3.39×10-2)、3号染色体的VEPH1(rs16827528, P=3.47×10-3)和18号染色体的MC4R (rs975918, P=2.79×102).在芯片阶段和重复验证阶段合并后的共计8415名研究对象中,一个位点到达全基因组显著水平CVEPH1, rs16827528,P=4.85×10-8)。对于已报道的两个位点FTO和MC4R,两阶段合并后均没有达到全基因组显著性水平(FTO, rsl7817712, P=1.05×10-5; MC4R, rs975918,P=8.72×10-7)。此外,我们还分析了以往报道的51个肥胖和体重指数位点在本研究芯片阶段的关联情况。除了前面提到的FTO和MC4R(?),还有8个位点与体重指数存在关联(P0.05)：TMEM18、SEC16B、GNPDA2、PCSK1、CDKAL1、MTCH2、GP2和NPC1、在其余41个位点中,有6个位点在汉族人群中为单态,35个位点未在本研究中发现与体重指数存在关联(P0.05)。结论本研究在中国汉族人群中发现1个新的体重指数位点(VEPH1)和4个潜在关联的位点(CMTM7, RPL18P9, GJA3和C14orfl77),此外还不同程度验证了10个以往研究报道的位点,包括FTO、MC4R、TMEM18、SEC16B、GNPDA2、 PCSK1、CDKAL1、MTCH2、GP2和NPC1(P值从4.42×10-2到8.72×10-7)。本研究发现的新位点需要进一步在不同人群中进行大规模重复验证,以验证关联结果的可靠性。对这些新位点进行精细定位和功能研究将有助于阐明体重指数和肥胖的遗传机制。
[Abstract]:The first part of the whole genome association study of the height of the Chinese Han population
Background and purpose
The height is mainly controlled by genetic factors, the genetic mechanism of 80%. is about the genetic research of height will contribute to further understanding of human growth and development. So far, most of the height of the genome-wide association study was carried out in the European population. Therefore, we China Han group conducted a genome-wide association study and repeated verification, to explore the genetic factors of height China Han population.
Research objects and methods
Chip stage of this research into the research and study of atherosclerosis atherosclerosis from Beijing Chinese 6534 research objects. The research of Beijing and Chinese atherosclerosis atherosclerosis research using Affymetrix GeneChip (?) 500K and AxiomTM genome CHB1 microarray for genotyping. Selection of chip stage reached genome-wide significance (P5.0 * 10-8) or the potential association (5 * 10-8P1.O * 10-5) sites in salt sensitive genetic epidemiology network (GenSalt) was replicated in the research of.GenSalt 1881 research objects using Affymetrix (?) 6 chip for genotyping.
Result
Through the chip phase of the meta analysis, we found two sites reached significant level. The whole genome of two loci were CYP19A1 loci have been reported in European populations (rs3751599, P=1.86 * 10-9) and ZNF638 were never reported (rs12612930, P=1.07 * 10-8). We selected 17 stages from chip sites were replicated in GenSalt. The chip stage and repeat the validation stage results after the merger, CYP19A1 and ZNF638 became associated with height is more significant (rs3751599, P = 4.80 * 10-10; rs12612930, P=2.02x10-10). In addition to the two sites, and the other 3 loci reached genome-wide significance which, 11q21 MAML2 (rs11021504, P=7.81 * 10-9) and 18q21.1 C18orf12 (rs11082671, P=1.87 * 10-8) is a newly discovered site, 12q13.3 CS (rs3816804, P=2.63 * 10-9) as reported sites. Therefore, in order to chip A total of 8415 segments and repeat validation stages were collected. We found three new height loci (ZNF638, MAML2 and C18orf12) and verified two reported loci (CS and CYP19A1).
We analyzed the correlation results of 8 loci have been reported in height in the Asian population in the chip phase of this study. All the 8 loci in this study effect in the direction with the previous Asian population studies reported in the same direction and 4 loci showed significant correlation (P0.05). The 4 loci of SNP were rs3791675 (EFEMP1, P=432 * 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). Similarly, we also evaluated other reports in the crowd in the research site height associated with height in the case, a total of 35 sites suggest that there is significant evidence of association in this study (P0.05).
conclusion
The study found that three new height related loci in the Han population, respectively ZNF638, MAML2 and C18orfl2. also verified the two previously reported loci, respectively CS and CYP19A1.. These findings suggest that the genetic mechanism of height in different ethnic groups have both the common and different points. Further research should be carried out to verify these loci in different populations and explain the underlying biological mechanisms.
The whole genome association study of body mass index in the second part of the Chinese Han population
Background and purpose
Obesity is an important public health problem in the world. So far, genome-wide association studies have found more than 50 with obesity and BMI associated sites. These sites are mostly found in European populations, only partially verified in Asian populations. There are some differences between different races suggesting that this genetic mechanism complex traits of body mass index, genome-wide association studies need to carry out body mass index in different ethnic groups and mutual verification. Therefore, in this study China Han population carried out a genome-wide association study of body mass index and replicated in an independent sample of genetic factors to explore the China Han population BMI.
Research objects and methods
6534 subjects were included in the study stage of the chip from the study of Beijing and Beijing China atherosclerosis atherosclerosis. Atherosclerosis study using GeneChip Affymetrix (?) 500K, Chinese atherosclerosis research using the AxiomTM whole genome CHB1 microarray for whole genome genotyping. The chip reached the potential association (P1.0 * 10-5) loci into repeated verification the analysis phase. Repeat verification using salt sensitive genetic epidemiology research network (GenSalt), 1881 subjects have been using Afymetrix (?) 6 chip for genotyping.
Result
The chip stage of 6534 subjects of the analysis, we found that the 7 loci of the P value is less than 1 * 10-5. of the 7 loci including two reported BMI related loci were FTO (rs17817712, P=3.21 * 10-6) and MC4R (rs975918, P=9.80 * 10-6), there are 5 new loci (CMTM7 rs347134, P=2.56, VEPH1 (rs16827528) * 10-6, P=3.97 * 10-6), RPL18P9 (rs12818806, P=2.98 * 10-6), GJA3 (rs4769965, P=1.17R10-6) and C14orf177 (rs17097110, P=5.92 * 10-6). We will be screened from the chip phase of these 7 loci associated with the strongest signal in the GenSalt study of SNP repeat the validation, including 3 in the repeated verification stage indicating significant evidence of Association (P0.05). The 3 SNP were located on chromosome 3 CMTM7 (rs347134, P=3.39 * 10-2), chromosome 3 VEPH1 (rs16827528, P= 3.47 * 10-3) and MC4R on chromosome 18 (rs975918, P=2.79 * 102). In the chip stage and repeat the validation stage after the merger of a total of 8415 subjects, a whole genome CVEPH1 loci reached significant level, rs16827528, P=4.85 * 10-8). For the reported two loci of FTO and MC4R, the two stage after the merger did not reach significant level of whole genome (FTO, rsl7817712, P=1.05 * 10-5; MC4R, rs975918, P=8.72 * 10-7).
In addition, we also analyzed the association of obesity and body mass index of 51 loci previously reported in the chip stage of this research. In addition to the previously mentioned FTO and MC4R (?), there are 8 loci associated with body mass index (P0.05) of:TMEM18, SEC16B, GNPDA2, PCSK1, CDKAL1, MTCH2, GP2 and NPC1. In the remaining 41 loci, 6 loci in Han population were the single state, 35 were not found associated with body mass index (P0.05) in this study.
conclusion
The study found that 1 new BMI loci in the Han population in Chinese (VEPH1) and 4 potential loci (CMTM7, RPL18P9, GJA3 and C14orfl77), in addition to different extent verified the 10 reported in previous research sites, including FTO, MC4R, TMEM18, SEC16B, GNPDA2, PCSK1, CDKAL1. MTCH2, GP2 and NPC1 (P value from 4.42 * 10-2 to 8.72 * 10-7). This study found that the new site needs further large-scale replication in different populations, which verifies the reliability of correlation results. Fine mapping and functional studies will help to elucidate the genetic mechanism of BMI and obesity in these new site.

【学位授予单位】：北京协和医学院
【学位级别】：博士
【学位授予年份】：2013
【分类号】：R181.33

【共引文献】