Germline sequence variation within the ribosomal DNA is associated with human complex traits

Ribosomal RNAs (rRNAs), essential components of the ribosome, are coded by the multi-copy ribosomal DNA (rDNA). Interestingly, rDNA displays substantial variation in all species, both as inter-individual differences in copy number (CN) and inter- and intragenomic sequence variation across copies (single-nucleotide variants [SNVs] and insertions/deletions [indels]). Whether germline rDNA sequence variation associates with human traits remains largely unknown. We here derive a stringently validated list of rDNA-associated SNVs and indels from UK Biobank whole-genome sequencing data, and we show that specific rDNA variants associate with human phenotypes independently of rDNA CN. Notably, variants within the 28S expansion segment 15L associate with body size traits. Variant combinations in the region present in actively translating ribosomes are predicted to alter the rRNA secondary structure. This represents the first large-scale association analysis of human traits with germline rDNA sequence variation, a largely ignored source of trait-relevant genetic variation to date.