Genomic Dissection of Population Substructure of Han Chinese and Its Implication in Association Studies

Abstract

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.

A panel of ancestry informative markers to estimate and correct potential effects of population stratification in Han Chinese

“…24 The estimated F ST value from this study is very close to a previously reported result (0.00116). 8 In addition, the average F ST between CHB and CHS from 1KG is 0.00145 (SD ¼ 0.00634), which is similar to our Affy6.0 data set. To identify genomic regions with highly differentiated allele frequencies between N-Han and S-Han, we examined the F ST distributions for all SNPs over the entire genome.…”

“…Previous studies have revealed one-dimensional 'north-south' population structure and no discernible east-west pattern were observed. [8][9][10] The north-south population structure is consistent with the historical migration and expansion pattern of the Han Chinese population. 23 Our Han Chinese samples were widely spread over PC1 (Figure 1a), suggesting a cryptic stratification in Han Chinese population.…”

“…Considering the intermarriages of Han Chinese from different parts of China and the fact that parts of our samples were from metropolitan cities, Anhui and Jiangsu which are located in mid-China, it was not easy to distinguish samples among N-Han, S-Han and the highly mixed central Han. 8 We used several strategies including geographical locations, PCA clustering and ingredient proportion in FRAPPE analysis to distinguish N-Han from S-Han. We first classified all the remaining samples into two groups based on the natural separation of northern and southern Mainland China by the Yangtze River.…”

“…However, population substructures are expected to exist in Han Chinese because of its complex ancestral origin, long history of interaction with many surrounding ethnic groups and recent migrations. Indeed, our previous study 8 and some other recent genome-wide studies 9,10 have revealed the complexity in Han Chinese population structure, particularly the north-south stratification. Therefore, a set of AIMs is required to discern the population stratification of Han Chinese and reduce the spurious associations.…”

Association between the angiotensinogen gene T174M polymorphism and hypertension risk in the Chinese population: a meta-analysis

“…The genetic background of the Chinese population was intricate owing to the large number of ethnicities included. Furthermore, some studies 49,50 indicate that the genetic profile of the Han Chinese is mixed, and heterogeneity could exist. Sensitivity analysis was performed to investigate the heterogeneity source in both the overall and the subgroup analyses.…”