Landscape of Tandem Repeat Variations in Multi-ethnic Asian Populations

Résumé fourni par la source

Abstract Tandem repeats (TRs) are implicated in over 70 Mendelian disorders and likely contribute to the “missing heritability” of complex traits and diseases, yet TR variations in Asian populations remain poorly characterized. Here, we constructed an Asian-specific SG10K-TR catalog by leveraging the SG10K_Health Dataset, comprising 916,274 autosomal TR loci genotyped in 9,490 individuals of Chinese (5,528), Malay (1,824), Indian (2,108), and other ancestries (30). Using a novel integrative measure for both repeat length and frequency variations, TRDDS, we found that population-level TR variations are selectively constrained in coding and promoter regions, whereas the enrichment of TRs with high population diversity was observed in regulatory sites with low chromatin accessibility and pathways related to neuronal functions. We also identified candidate TRs under selection that predominantly targets neuronal and synaptic architecture. Analysis of linkage disequilibrium (LD) patterns revealed that TRs are often poorly tagged by small variants, although we identified 123 candidate functional TRs that may underlie association signals previously attributed to nearby noncoding SNPs. Finally, TR-based GWAS of six anthropometric and lipid traits identified ten loci with genome-wide significant associations, including two novel loci for BMI ( LINC02817 ) and height ( UNC45B ), and a TR variant as causal candidate for a known GWAS locus at HMGCR for LDL. Together, this study establishes a critical Asian-specific TR resource and highlights the fundamental role of TR diversity in driving evolutionary neuroplasticity and shaping the genetic architecture of complex traits.

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