Genomic dissection of population substructure of Han Chinese and its implication in association studies.
To date, most genome-wide association studies (GWAS) and studies of fine-scale population structure have been conducted primarily on Europeans. Han Chinese, the largest ethnic group in the world, composing 20% of the entire global human population, is largely underrepresented in such studies. A well-recognized challenge is the fact that population structure can cause spurious associations in GWAS. In this study, we examined population substructures in a diverse set of over 1700 Han Chinese samples collected from 26 regions across China, each genotyped at approximately 160K single-nucleotide polymorphisms (SNPs). Our results showed that the Han Chinese population is intricately substructured, with the main observed clusters corresponding roughly to northern Han, central Han, and southern Han. However, simulated case-control studies showed that genetic differentiation among these clusters, although very small (F(ST) = 0.0002 approximately 0.0009), is sufficient to lead to an inflated rate of false-positive results even when the sample size is moderate. The top two SNPs with the greatest frequency differences between the northern Han and southern Han clusters (F(ST) > 0.06) were found in the FADS2 gene, which associates with the fatty acid composition in phospholipids, and in the HLA complex P5 gene (HCP5), which associates with HIV infection, psoriasis, and psoriatic arthritis. Ingenuity Pathway Analysis (IPA) showed that most differentiated genes among clusters are involved in cardiac arteriopathy (p < 10(-101)). These signals indicating significant differences among Han Chinese subpopulations should be carefully explained in case they are also detected in association studies, especially when sample sources are diverse.
Xu
Shuhua
S
Chinese Academy of Sciences and Max Planck Society Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, PR China.
Yin
Xianyong
X
Li
Shilin
S
Jin
Wenfei
W
Lou
Haiyi
H
Yang
Ling
L
Gong
Xiaohong
X
Wang
Hongyan
H
Shen
Yiping
Y
Pan
Xuedong
X
He
Yungang
Y
Yang
Yajun
Y
Wang
Yi
Y
Fu
Wenqing
W
An
Yu
Y
Wang
Jiucun
J
Tan
Jingze
J
Qian
Ji
J
Chen
Xiaoli
X
Zhang
Xin
X
Sun
Yangfei
Y
Zhang
Xuejun
X
Wu
Bailin
B
Jin
Li
L
D015535:Arthritis, Psoriatic / Q000235:genetics; D044466:Asian People; D002681:China; D005006:Ethnicity; D005189:False Positive Reactions; D044943:Fatty Acid Desaturases / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics*; D005828:Genetics, Population; D006331:Heart Diseases / Q000235:genetics; D006801:Humans; D008285:Major Histocompatibility Complex / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D025341:Principal Component Analysis; D011565:Psoriasis / Q000235:genetics; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated
C080521:HCP5 long noncoding RNA, human; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D044943:Fatty Acid Desaturases; C533241:FADS2 protein, human