TY - JOUR
T1 - A phenome-wide association study identifies effects of copy-number variation of VNTRs and multicopy genes on multiple human traits
AU - Garg, Paras
AU - Jadhav, Bharati
AU - Lee, William
AU - Rodriguez, Oscar L.
AU - Martin-Trujillo, Alejandro
AU - Sharp, Andrew J.
N1 - Publisher Copyright:
© 2022 American Society of Human Genetics
PY - 2022/6/2
Y1 - 2022/6/2
N2 - The human genome contains tens of thousands of large tandem repeats and hundreds of genes that show common and highly variable copy-number changes. Due to their large size and repetitive nature, these variable number tandem repeats (VNTRs) and multicopy genes are generally recalcitrant to standard genotyping approaches and, as a result, this class of variation is poorly characterized. However, several recent studies have demonstrated that copy-number variation of VNTRs can modify local gene expression, epigenetics, and human traits, indicating that many have a functional role. Here, using read depth from whole-genome sequencing to profile copy number, we report results of a phenome-wide association study (PheWAS) of VNTRs and multicopy genes in a discovery cohort of ∼35,000 samples, identifying 32 traits associated with copy number of 38 VNTRs and multicopy genes at 1% FDR. We replicated many of these signals in an independent cohort and observed that VNTRs showing trait associations were significantly enriched for expression QTLs with nearby genes, providing strong support for our results. Fine-mapping studies indicated that in the majority (∼90%) of cases, the VNTRs and multicopy genes we identified represent the causal variants underlying the observed associations. Furthermore, several lie in regions where prior SNV-based GWASs have failed to identify any significant associations with these traits. Our study indicates that copy number of VNTRs and multicopy genes contributes to diverse human traits and suggests that complex structural variants potentially explain some of the so-called “missing heritability” of SNV-based GWASs.
AB - The human genome contains tens of thousands of large tandem repeats and hundreds of genes that show common and highly variable copy-number changes. Due to their large size and repetitive nature, these variable number tandem repeats (VNTRs) and multicopy genes are generally recalcitrant to standard genotyping approaches and, as a result, this class of variation is poorly characterized. However, several recent studies have demonstrated that copy-number variation of VNTRs can modify local gene expression, epigenetics, and human traits, indicating that many have a functional role. Here, using read depth from whole-genome sequencing to profile copy number, we report results of a phenome-wide association study (PheWAS) of VNTRs and multicopy genes in a discovery cohort of ∼35,000 samples, identifying 32 traits associated with copy number of 38 VNTRs and multicopy genes at 1% FDR. We replicated many of these signals in an independent cohort and observed that VNTRs showing trait associations were significantly enriched for expression QTLs with nearby genes, providing strong support for our results. Fine-mapping studies indicated that in the majority (∼90%) of cases, the VNTRs and multicopy genes we identified represent the causal variants underlying the observed associations. Furthermore, several lie in regions where prior SNV-based GWASs have failed to identify any significant associations with these traits. Our study indicates that copy number of VNTRs and multicopy genes contributes to diverse human traits and suggests that complex structural variants potentially explain some of the so-called “missing heritability” of SNV-based GWASs.
KW - CNV
KW - GWAS
KW - read depth
KW - tandem repeat
KW - variable number tandem repeat
UR - http://www.scopus.com/inward/record.url?scp=85131083201&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2022.04.016
DO - 10.1016/j.ajhg.2022.04.016
M3 - Article
C2 - 35609568
AN - SCOPUS:85131083201
SN - 0002-9297
VL - 109
SP - 1065
EP - 1076
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 6
ER -