Multi-ancestry tandem repeat association study of hair colour using exome-wide sequencing.

Hair colour variation is influenced by hundreds of positions across the human genome but this genetic contribution has only been narrowly explored. Genome-wide association studies identified single nucleotide polymorphisms (SNPs) influencing hair colour but the biology underlying these associations is challenging to interpret. We report 16 tandem repeats (TRs) with effects on different models of hair colour plus two TRs associated with hair colour in diverse ancestry groups. Several of these TRs expand or contract amino acid coding regions of their localized protein such that structure, and by extension function, may be altered. We also demonstrate that independent of SNP variation, these TRs can be used to great an additive polygenic score that predicts darker hair colour. This work adds to the growing body of evidence regarding TR influence on human traits with relatively large and independent effects relative to surrounding SNP variation.

Exome-wide tandem repeats confer large effects on subcortical volumes in UK Biobank participants.

The human subcortex is involved in memory and cognition. Structural and functional changes in subcortical regions is implicated in psychiatric conditions. We performed an association study of subcortical volumes using 15,941 tandem repeats (TRs) derived from whole exome sequencing (WES) data in 16,527 unrelated European ancestry participants. We identified 17 loci, most of which were associated with accumbens volume, and nine of which had fine-mapping probability supporting their causal effect on subcortical volume independent of surrounding variation. The most significant association involved NTN1 -[GCGG] N and increased accumbens volume (ß=5.93, P=8.16x10 -9 ). Three exonic TRs had large effects on thalamus volume ( LAT2 -[CATC] N ß=-949, P=3.84x10 -6 and SLC39A4 -[CAG] N ß=-1599, P=2.42x10 -8 ) and pallidum volume ( MCM2 -[AGG] N ß=-404.9, P=147x10 -7 ). These genetic effects were consistent measurements of per-repeat expansion/contraction effects on organism fitness. With 3-dimensional modeling, we reinforced these effects to show that the expanded and contracted LAT2 -[CATC] N repeat causes a frameshift mutation that prevents appropriate protein folding. These TRs also exhibited independent effects on several psychiatric symptoms, including LAT2 -[CATC] N and the tiredness/low energy symptom of depression (ß=0.340, P=0.003). These findings link genetic variation to tractable biology in the brain and relevant psychiatric symptoms. We also chart one pathway for TR prioritization in future complex trait genetic studies.