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.