Contribution of rare whole-genome sequencing variants to plasma protein levels and the missing heritability

Marcin Kierczak, Nima Rafati, Julia Höglund, Hadrien Gourlé, Valeria Lo Faro, Daniel Schmitz, Weronica E. Ek, Ulf Gyllensten, Stefan Enroth, Diana Ekman, Björn Nystedt, Torgny Karlsson and Åsa Johansson ()
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Marcin Kierczak: Uppsala University
Nima Rafati: Uppsala University
Julia Höglund: Uppsala University
Hadrien Gourlé: Uppsala University
Valeria Lo Faro: Uppsala University
Daniel Schmitz: Uppsala University
Weronica E. Ek: Uppsala University
Ulf Gyllensten: Uppsala University
Stefan Enroth: Uppsala University
Diana Ekman: Stockholm University
Björn Nystedt: Uppsala University
Torgny Karlsson: Uppsala University
Åsa Johansson: Uppsala University

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: Abstract Despite the success of genome-wide association studies, much of the genetic contribution to complex traits remains unexplained. Here, we analyse high coverage whole-genome sequencing data, to evaluate the contribution of rare genetic variants to 414 plasma proteins. The frequency distribution of genetic variants is skewed towards the rare spectrum, and damaging variants are more often rare. We estimate that less than 4.3% of the narrow-sense heritability is expected to be explained by rare variants in our cohort. Using a gene-based approach, we identify Cis-associations for 237 of the proteins, which is slightly more compared to a GWAS (N = 213), and we identify 34 associated loci in Trans. Several associations are driven by rare variants, which have larger effects, on average. We therefore conclude that rare variants could be of importance for precision medicine applications, but have a more limited contribution to the missing heritability of complex diseases.

Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30208-8

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DOI: 10.1038/s41467-022-30208-8

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