由18425名臺灣成年人全基因組關聯研究所發現的身高關聯新基因

Novel height-associated genes identified by a genome-wide association study in 18425 Taiwanese adults

李昱陞(Yu-Sheng Lee)

指導教授 ： 林菀俞

國立臺灣大學/公共衛生學院/流行病學與預防醫學研究所/碩士(2019年)

https://doi.org/10.6342/NTU201903301

摘要

人類的身高屬多基因遺傳，由多個基因調控，且可能因不同人種而異。於歐洲人之全基因組關聯研究辨識出約莫700個與身高相關的單核甘酸多型性(SNPs)。然迄今，針對漢民族進行的全基因組關聯研究相對較少。因此，本研究中，吾人以「臺灣人體生物資料庫」的18,425位獨立個案、587,845個來自體染色體的SNPs進行人類身高的全基因組關聯研究。個案多來自於漢民族。為了尋找出與身高關聯的SNPs，吾人以身高對每一個SNP配適一條迴歸式，並調整性別、年齡、與前十個主成分。共114個SNPs達全基因組關聯研究之顯著水準(P < 5×〖10〗^(-8))，分別坐落於43個基因座上。這114個SNPs中有26個SNPs曾被過去文獻發表過。587,845個體染色體SNPs解釋46.7%的身高變異。
在這114個SNPs當中，與身高增加有關的等位基因頻率平均值為0.48，根據「千人基因組計劃」(1000 Genomes Project)的歐裔族群資料，這些等位基因頻率平均值則為0.57。其中值得注意的SNPs分別為rs3782886、rs671、rs78069066、rs77768175、rs11066280、與rs77753011。歐裔族群在這六個SNPs中與身高增加有關的等位基因頻率其平均值皆為1，然在「臺灣人體生物資料庫」中則僅有0.71。與這六個SNPs鄰近的基因座則分別為ACAD10、BRAP、ALDH2、MIR6761、ADAM1A、MAPKAPK5與HECTD4。BRAP基因（BRCA1相關蛋白）將負調節MAP激酶的活化。而MAP激酶則屬於MAPK路徑，該激酶會調節細胞內的信號傳遞。當細胞膜接收到有絲分裂原的信號時，若MAPK路徑異常，將導致個體表現出較為矮小的身材。這或許能說明為何歐裔族群普遍高於漢民族。
在PrediXcan結果的部分，於顯著水準 2.5×〖10〗^(-6) 之下，48個人體組織共有59個基因達顯著。其中出現頻率較高的基因有ATXN3、CEP250、DCAF16、TRIP11、UQCC1、CPSF2、RP3-477O4.16，除了最後一個基因類型屬長鏈非編碼的核醣核酸(LincRNA)，其餘皆屬吾人所發現的43個基因。PrediXcan的結果進一步支持吾人於全基因組關聯研究之發現。

關鍵字

全基因組關聯研究 ； 身高 ； 多基因遺傳 ； 基因水平關聯檢定 ； 臺灣人體生物資料庫

並列摘要

Human body height is very polygenic, controlled by multiple genes that may be diverse in different ethnicity populations. Previous genome-wide association studies (GWASs) have identified ~700 nearly independent height-associated single-nucleotide polymorphisms (SNPs) in Europeans. However, to date, few GWASs have been focused on Han Chinese. With 18425 unrelated adults from the Taiwan Biobank (TWB), 587845 autosomal SNPs from each adult, we here conducted a GWAS on human body height. Most TWB subjects are of Han Chinese ancestry. To identify height-associated SNPs, we regressed body height on each SNP, while adjusting for sex, age, and the first 10 ancestry principal components. A total of 114 SNPs from 43 independent loci achieved the genome-wide significance level (P < 5×〖10〗^(-8)). Among the 114 SNPs, 26 have been reported to be associated with body height by previous studies. All the 587845 autosomal SNPs explained ~46.7% variation in human body height.
Among these 114 height-associated SNPs, the average of height-increasing allele frequencies in TWB is 0.48, whereas 0.57 is presented in Europeans according to the 1000 Genomes Project. Notably, at 6 SNPs, including rs3782886, rs671, rs78069066, rs77768175, rs11066280, and rs77753011, the frequencies of height-increasing alleles at these 6 SNPs are all 1 in Europeans. By contrast, in TWB, the mean frequency of height-increasing alleles at these 6 SNPs is only 0.71. Seven genes near the 6 SNPs, including ACAD10, BRAP, ALDH2, MIR6761, ADAM1A, MAPKAPK5, and HECTD4. BRAP gene (BRCA1-associated protein) would negatively regulate MAP kinase activation. MAP kinase belongs to MAPK pathway, and it communicates signals from a receptor. When an extracellular mitogen binds to the membrane receptor, an abnormal MAPK pathway would result in short stature. This may explain why Europeans are generally taller than Han Chinese.
PrediXcan identified 59 significant genes from 48 human tissues (P < 2.5×〖10〗^(-6)). Among these 59 genes, ATXN3、CEP250、DCAF16、TRIP11、UQCC1、CPSF2、RP3-477O4.16 were found to be significant in more than 10 tissues. These genes belong to the 43 genes identified from our GWAS, except RP3-477O4.16 that is Long intergenic non-coding RNA (LincRNA). These results from PrediXcan further support our findings from GWAS on human body height.

並列關鍵字

Genome-wide association study ； Human body height ； Polygenic inheritance ； Gene-based association testing ； Taiwan biobank

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