Isoform-Level Transcriptome-Wide Association Uncovers Genetic Risk Mechanisms for Neuropsychiatric Disorders in the Human Brain

Authors

Arjun Bhattacharya
Daniel D Vo
Connor Jops
Minsoo Kim
Cindy Wen
Jonatan L Hervoso
Bogdan Pasaniuc
Michael J Gandal

Publication Date

12-1-2023

Journal

Nature Genetics

Abstract

Methods integrating genetics with transcriptomic reference panels prioritize risk genes and mechanisms at only a fraction of trait-associated genetic loci, due in part to an overreliance on total gene expression as a molecular outcome measure. This challenge is particularly relevant for the brain, in which extensive splicing generates multiple distinct transcript-isoforms per gene. Due to complex correlation structures, isoform-level modeling from cis-window variants requires methodological innovation. Here we introduce isoTWAS, a multivariate, stepwise framework integrating genetics, isoform-level expression and phenotypic associations. Compared to gene-level methods, isoTWAS improves both isoform and gene expression prediction, yielding more testable genes, and increased power for discovery of trait associations within genome-wide association study loci across 15 neuropsychiatric traits. We illustrate multiple isoTWAS associations undetectable at the gene-level, prioritizing isoforms of AKT3, CUL3 and HSPD1 in schizophrenia and PCLO with multiple disorders. Results highlight the importance of incorporating isoform-level resolution within integrative approaches to increase discovery of trait associations, especially for brain-relevant traits.

Keywords

Humans, Transcriptome, Genome-Wide Association Study, Quantitative Trait Loci, Genetic Predisposition to Disease, Brain, Protein Isoforms, Polymorphism, Single Nucleotide

DOI

10.1038/s41588-023-01560-2

PMID

38036788

PMCID

PMC10703692

PubMedCentral® Posted Date

November 2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes