發(fā)布時(shí)間：2018-01-01 16:06

  本文關(guān)鍵詞：中國(guó)漢族人群身高和體重指數(shù)的全基因組關(guān)聯(lián)研究　出處：《北京協(xié)和醫(yī)學(xué)院》2013年博士論文　論文類型：學(xué)位論文

  更多相關(guān)文章： 中國(guó)漢族人群 體重指數(shù) 全基因組關(guān)聯(lián)研究 VEPH1 FTO MC4R

【摘要】：第一部分中國(guó)漢族人群身高的全基因組關(guān)聯(lián)研究 背景和目的 身高主要受遺傳因素控制,其遺傳度約為80%。研究身高的遺傳機(jī)制將有助于深入理解人類生長(zhǎng)發(fā)育過程。到目前為止,大部分身高的全基因組關(guān)聯(lián)研究是在歐洲人群開展的。因此,我們?cè)谥袊?guó)漢族人群中開展了這項(xiàng)全基因組關(guān)聯(lián)研究并進(jìn)行重復(fù)驗(yàn)證,來探討中國(guó)漢族人群身高的遺傳因素。 研究對(duì)象和方法 本研究的芯片階段納入了來自北京動(dòng)脈粥樣硬化研究和中國(guó)動(dòng)脈粥樣硬化研究的6534名研究對(duì)象。北京動(dòng)脈粥樣硬化研究和中國(guó)動(dòng)脈粥樣硬化研究分別使用Affymetrix的GeneChip(?)500K和AxiomTM全基因組CHB1陣列芯片進(jìn)行基因分型。挑選芯片階段達(dá)到全基因組顯著性(P5.0×10-8)或潛在關(guān)聯(lián)(5.0×10-8P1.O×10-5)的位點(diǎn)在鹽敏感性遺傳流行病學(xué)網(wǎng)絡(luò)(GenSalt)研究中進(jìn)行重復(fù)驗(yàn)證。GenSalt的1881名研究對(duì)象使用Affymetrix(?)6.0芯片進(jìn)行基因分型。 結(jié)果 通過芯片階段的meta分析,我們發(fā)現(xiàn)了兩個(gè)位點(diǎn)達(dá)到全基因組顯著水平。這兩個(gè)位點(diǎn)分別是歐洲人群中已報(bào)道的CYP19A1位點(diǎn)(rs3751599, P=1.86×10-9)和從未報(bào)道過的ZNF638位點(diǎn)(rs12612930,P=1.07×10-8)。我們從芯片階段選擇了17個(gè)位點(diǎn)在GenSalt研究中進(jìn)行了重復(fù)驗(yàn)證。將芯片階段和重復(fù)驗(yàn)證階段結(jié)果合并后,CYP19A1和ZNF638與身高的關(guān)聯(lián)變得更為顯著(rs3751599,P＝4.80×10-10；rs12612930,P=2.02x10-10)。除這兩個(gè)位點(diǎn)外,還有其它3個(gè)位點(diǎn)達(dá)到了全基因組顯著性。其中,11q21的MAML2(rs11021504,P=7.81×10-9)和18q21.1的C18orf12(rs11082671,P=1.87×10-8)為新發(fā)現(xiàn)的位點(diǎn),12q13.3的CS(rs3816804,P=2.63×10-9)為已報(bào)道過的位點(diǎn)。因此,在將芯片階段和重復(fù)驗(yàn)證階段合并共計(jì)8415研究對(duì)象中,我們發(fā)現(xiàn)了三個(gè)新的身高位點(diǎn)(ZNF638、MAML2和C18orf12)并驗(yàn)證了兩個(gè)已報(bào)道的位點(diǎn)(CS和CYP19A1)。 我們分析了亞洲人群中已報(bào)道的8個(gè)身高位點(diǎn)在本研究芯片階段的關(guān)聯(lián)結(jié)果。所有8個(gè)位點(diǎn)在本研究中的效應(yīng)方向均與以往亞洲人群研究報(bào)道的方向相同并且4個(gè)位點(diǎn)顯示顯著關(guān)聯(lián)(P0.05)。這4個(gè)位點(diǎn)的SNP分別為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)。同樣,我們也評(píng)估了其他人群中報(bào)道的身高位點(diǎn)在本研究中與身高的關(guān)聯(lián)情況,共有35個(gè)位點(diǎn)在本研究中提示有顯著關(guān)聯(lián)的證據(jù)(P0.05)。 結(jié)論 本研究在漢族人群中發(fā)現(xiàn)了三個(gè)新的身高相關(guān)位點(diǎn),分別為ZNF638、MAML2和C18orfl2。此外還驗(yàn)證了兩個(gè)以往報(bào)道的位點(diǎn),分別為CS和CYP19A1。這些研究結(jié)果表明,身高的遺傳機(jī)制在不同人種之間既有共同又有不同之處。應(yīng)當(dāng)開展進(jìn)一步研究對(duì)這些位點(diǎn)在不同人群中進(jìn)行驗(yàn)證并解釋其潛在的生物學(xué)機(jī)制。 第二部分中國(guó)漢族人群體重指數(shù)的全基因組關(guān)聯(lián)研究 背景和目的 肥胖是全球重要的公共衛(wèi)生問題。目前為止,全基因組關(guān)聯(lián)研究已經(jīng)發(fā)現(xiàn)50多個(gè)與肥胖和體重指數(shù)相關(guān)聯(lián)的位點(diǎn)。這些位點(diǎn)大多是在歐洲人群中發(fā)現(xiàn)的,僅有部分在亞洲人群中得到驗(yàn)證。這提示體重指數(shù)這一復(fù)雜性狀的遺傳機(jī)制在不同種族之間有一定的差異,需要在不同種族中開展體重指數(shù)的全基因組關(guān)聯(lián)研究并相互驗(yàn)證。因此,本研究在中國(guó)漢族人群中開展體重指數(shù)全基因組關(guān)聯(lián)研究并在獨(dú)立樣本中進(jìn)行重復(fù)驗(yàn)證,來探討中國(guó)漢族人群體重指數(shù)的遺傳因素。 研究對(duì)象和方法 本研究芯片階段納入的6534名研究對(duì)象分別來自北京動(dòng)脈粥樣硬化研究和中國(guó)動(dòng)脈粥樣硬化研究。北京動(dòng)脈粥樣硬化研究使用Affymetrix的GeneChip(？)500K,中國(guó)動(dòng)脈粥樣硬化研究使用AxiomTM全基因組CHB1陣列芯片進(jìn)行全基因組基因分型。芯片階段達(dá)到潛在關(guān)聯(lián)(P1.0×10-5)的位點(diǎn)進(jìn)入重復(fù)驗(yàn)證分析階段。重復(fù)驗(yàn)證采用鹽敏感性遺傳流行病學(xué)網(wǎng)絡(luò)(GenSalt)研究,1881名研究對(duì)象已使用Afymetrix(?)6.0芯片進(jìn)行基因分型。 結(jié)果 通過對(duì)6534名研究對(duì)象的芯片階段分析,我們發(fā)現(xiàn)7個(gè)位點(diǎn)的P值小于1×10-5。這7個(gè)位點(diǎn)包括兩個(gè)已報(bào)道的體重指數(shù)相關(guān)位點(diǎn)分別為FTO(rs17817712,P=3.21×10-6)和MC4R (rs975918, P=9.80×10-6),還有5個(gè)新位點(diǎn)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)。我們將從芯片階段篩選出的這7個(gè)位點(diǎn)關(guān)聯(lián)信號(hào)最強(qiáng)的SNP在GenSalt研究中進(jìn)行了重復(fù)驗(yàn)證,其中3個(gè)在重復(fù)驗(yàn)證階段提示有顯著關(guān)聯(lián)證據(jù)(P0.05)。這3個(gè)SNP分別位于3號(hào)染色體的CMTM7(rs347134, P=3.39×10-2)、3號(hào)染色體的VEPH1(rs16827528, P=3.47×10-3)和18號(hào)染色體的MC4R (rs975918, P=2.79×102).在芯片階段和重復(fù)驗(yàn)證階段合并后的共計(jì)8415名研究對(duì)象中,一個(gè)位點(diǎn)到達(dá)全基因組顯著水平CVEPH1, rs16827528,P=4.85×10-8)。對(duì)于已報(bào)道的兩個(gè)位點(diǎn)FTO和MC4R,兩階段合并后均沒有達(dá)到全基因組顯著性水平(FTO, rsl7817712, P=1.05×10-5; MC4R, rs975918,P=8.72×10-7)。 此外,我們還分析了以往報(bào)道的51個(gè)肥胖和體重指數(shù)位點(diǎn)在本研究芯片階段的關(guān)聯(lián)情況。除了前面提到的FTO和MC4R(?),還有8個(gè)位點(diǎn)與體重指數(shù)存在關(guān)聯(lián)(P0.05)：TMEM18、SEC16B、GNPDA2、PCSK1、CDKAL1、MTCH2、GP2和NPC1、在其余41個(gè)位點(diǎn)中,有6個(gè)位點(diǎn)在漢族人群中為單態(tài),35個(gè)位點(diǎn)未在本研究中發(fā)現(xiàn)與體重指數(shù)存在關(guān)聯(lián)(P0.05)。 結(jié)論 本研究在中國(guó)漢族人群中發(fā)現(xiàn)1個(gè)新的體重指數(shù)位點(diǎn)(VEPH1)和4個(gè)潛在關(guān)聯(lián)的位點(diǎn)(CMTM7, RPL18P9, GJA3和C14orfl77),此外還不同程度驗(yàn)證了10個(gè)以往研究報(bào)道的位點(diǎn),包括FTO、MC4R、TMEM18、SEC16B、GNPDA2、 PCSK1、CDKAL1、MTCH2、GP2和NPC1(P值從4.42×10-2到8.72×10-7)。本研究發(fā)現(xiàn)的新位點(diǎn)需要進(jìn)一步在不同人群中進(jìn)行大規(guī)模重復(fù)驗(yàn)證,以驗(yàn)證關(guān)聯(lián)結(jié)果的可靠性。對(duì)這些新位點(diǎn)進(jìn)行精細(xì)定位和功能研究將有助于闡明體重指數(shù)和肥胖的遺傳機(jī)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.

【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2013
【分類號(hào)】：R181.33

【共引文獻(xiàn)】

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本文編號(hào)：1365205