Whole-genome sequencing analysis identifies rare, large-effect noncoding variants and regulatory regions associated with circulating protein levels. Nat Genet (2025)

Hawkes, G., Chundru, K., Jackson, L. et al. Whole-genome sequencing analysis identifies rare, large-effect noncoding variants and regulatory regions associated with circulating protein levels. Nat Genet 57, 626–634 (2025). https://doi.org/10.1038/s41588-025-02095-4  

 

앞서 나온 Dhindsa, R.S., Burren, O.S., Sun, B.B. et al. Rare variant associations with plasma protein levels in the UK Biobank. Nature 622, 339–347 (2023). https://doi.org/10.1038/s41586-023-06547-x 와 뭐가 다른지 봤더니 

앞에서는 WES 데이터를 사용해 coding region의 rare variant를 본 반면, 여기서는 WGS 데이터를 사용해, non-coding region의 rare variant를 봤다.

 

Abstract

The contribution of rare noncoding genetic variation to common phenotypes is largely unknown, as a result of a historical lack of population-scale whole-genome sequencing data and the difficulty of categorizing noncoding variants into functionally similar groups. To begin addressing these challenges, we performed a cis association analysis using whole-genome sequencing data, consisting of 1.1 billion variants, 123 million noncoding aggregate-based tests and 2,907 circulating protein levels in ~50,000 UK Biobank participants. We identified 604 independent rare noncoding single-variant associations with circulating protein levels. Unlike protein-coding variation, rare noncoding genetic variation was almost as likely to increase or decrease protein levels. Rare noncoding aggregate testing identified 357 conditionally independent associated regions. Of these, 74 (21%) were not detectable by single-variant testing alone. Our findings have important implications for the identification, and role, of rare noncoding genetic variation associated with common human phenotypes, including the importance of testing aggregates of noncoding variants.