PT  - JOURNAL ARTICLE
AU  - Minhui Chen
AU  - Carlo Sidore
AU  - Masato Akiyama
AU  - Kazuyoshi Ishigaki
AU  - Yoichiro Kamatani
AU  - David Schlessinger
AU  - Francesco Cucca
AU  - Yukinori Okada
AU  - Charleston W. K. Chiang
TI  - Evidence of polygenic adaptation at height-associated loci in mainland Europeans and Sardinians
AID  - 10.1101/776377
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 776377
4099  - http://biorxiv.org/content/early/2019/09/19/776377.short
4100  - http://biorxiv.org/content/early/2019/09/19/776377.full
AB  - Adult height was one of the earliest putative examples of polygenic adaptation in human. By constructing polygenic height scores using effect sizes and frequencies from hundreds of genomic loci robustly associated with height, it was reported that Northern Europeans were genetically taller than Southern Europeans beyond neutral expectation. However, this inference was recently challenged. Sohail et al. and Berg et al. showed that the polygenic signature disappeared if summary statistics from UK Biobank (UKB) were used in the analysis, suggesting that residual uncorrected stratification from large-scale consortium studies was responsible for the previously noted genetic difference. It thus remains an open question whether height loci exhibit signals of polygenic adaptation in any human population. In the present study, we re-examined this question, focusing on one of the shortest European populations, the Sardinians, as well as on the mainland European populations in general. We found that summary statistics from UKB significantly correlate with population structure in Europe. To further alleviate concerns of biased ascertainment of GWAS loci, we examined height-associated loci from the Biobank of Japan (BBJ). Applying frequency-based inference over these height-associated loci, we showed that the Sardinians remain significantly shorter than expected (~ 0.35 standard deviation shorter than CEU based on polygenic height scores, P = 1.95e-6). We also found the trajectory of polygenic height scores decreased over at least the last 10,000 years when compared to the British population (P = 0.0123), consistent with a signature of polygenic adaptation at height-associated loci. Although the same approach showed a much subtler signature in mainland European populations, we found a clear and robust adaptive signature in UK population using a haplotype-based statistic, tSDS, driven by the height-increasing alleles (P = 4.8e-4). In summary, by examining frequencies at height loci ascertained in a distant East Asian population, we further supported the evidence of polygenic adaptation at height-associated loci among the Sardinians. In mainland Europeans, we also found an adaptive signature, although becoming more pronounced only in haplotype-based analysis.