TY - JOUR
T1 - Multi-omic quantitative trait loci link tandem repeat size variation to gene regulation in human brain
AU - Cui, Ya
AU - Arnold, Frederick J.
AU - Li, Jason Sheng
AU - Wu, Jie
AU - Wang, Dan
AU - Philippe, Julien
AU - Colwin, Michael R.
AU - Michels, Sebastian
AU - Chen, Chaorong
AU - Sallam, Tamer
AU - Thompson, Leslie M.
AU - La Spada, Albert R.
AU - Li, Wei
N1 - Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature America, Inc. 2025.
PY - 2025/2
Y1 - 2025/2
N2 - Tandem repeat (TR) size variation is implicated in ~50 neurological disorders, yet its impact on gene regulation in the human brain remains largely unknown. In the present study, we quantified the impact of TR size variation on brain gene regulation across distinct molecular phenotypes, based on 4,412 multi-omics samples from 1,597 donors, including 1,586 newly sequenced ones. We identified ~2.2 million TR molecular quantitative trait loci (TR-xQTLs), linking ~139,000 unique TRs to nearby molecular phenotypes, including many known disease-risk TRs, such as the G2C4 expansion in C9orf72 associated with amyotrophic lateral sclerosis. Fine-mapping revealed ~18,700 TRs as potential causal variants. Our in vitro experiments further confirmed the causal and independent regulatory effects of three TRs. Additional colocalization analysis indicated the potential causal role of TR variation in brain-related phenotypes, highlighted by a 3ʹ-UTR TR in NUDT14 linked to cortical surface area and a TG repeat in PLEKHA1, associated with Alzheimer’s disease.
AB - Tandem repeat (TR) size variation is implicated in ~50 neurological disorders, yet its impact on gene regulation in the human brain remains largely unknown. In the present study, we quantified the impact of TR size variation on brain gene regulation across distinct molecular phenotypes, based on 4,412 multi-omics samples from 1,597 donors, including 1,586 newly sequenced ones. We identified ~2.2 million TR molecular quantitative trait loci (TR-xQTLs), linking ~139,000 unique TRs to nearby molecular phenotypes, including many known disease-risk TRs, such as the G2C4 expansion in C9orf72 associated with amyotrophic lateral sclerosis. Fine-mapping revealed ~18,700 TRs as potential causal variants. Our in vitro experiments further confirmed the causal and independent regulatory effects of three TRs. Additional colocalization analysis indicated the potential causal role of TR variation in brain-related phenotypes, highlighted by a 3ʹ-UTR TR in NUDT14 linked to cortical surface area and a TG repeat in PLEKHA1, associated with Alzheimer’s disease.
UR - https://www.scopus.com/pages/publications/85217256391
U2 - 10.1038/s41588-024-02057-2
DO - 10.1038/s41588-024-02057-2
M3 - Article
C2 - 39809899
AN - SCOPUS:85217256391
SN - 1061-4036
VL - 57
SP - 369
EP - 378
JO - Nature Genetics
JF - Nature Genetics
IS - 2
M1 - 2927
ER -