A Phenome-wide Association Study of Methylated GC-rich Repeats Identifies a GCC Repeat Expansion in AFF3 Associated with Intellectual Disability

Overview

Journal Nat Genet

Specialty Genetics

Date 2024 Sep 23

PMID 39313615

Authors

Bharati Jadhav

Paras Garg

Joke J F A van Vugt

Kristina Ibanez

Delia Gagliardi

William Lee

Mariya Shadrina

Tom Mokveld

Egor Dolzhenko

Alejandro Martin-Trujillo

Scott J Gies

Gabrielle Altman

Clarissa Rocca

Mafalda Barbosa

Miten Jain

Nayana Lahiri

Katherine Lachlan

Henry Houlden

Benedict Paten

Jan Veldink

Arianna Tucci

Andrew J Sharp

Affiliations

Soon will be listed here.

Abstract

GC-rich tandem repeat expansions (TREs) are often associated with DNA methylation, gene silencing and folate-sensitive fragile sites, and underlie several congenital and late-onset disorders. Through a combination of DNA-methylation profiling and tandem repeat genotyping, we identified 24 methylated TREs and investigated their effects on human traits using phenome-wide association studies in 168,641 individuals from the UK Biobank, identifying 156 significant TRE-trait associations involving 17 different TREs. Of these, a GCC expansion in the promoter of AFF3 was associated with a 2.4-fold reduced probability of completing secondary education, an effect size comparable to several recurrent pathogenic microdeletions. In a cohort of 6,371 probands with neurodevelopmental problems of suspected genetic etiology, we observed a significant enrichment of AFF3 expansions compared with controls. With a population prevalence that is at least fivefold higher than the TRE that causes fragile X syndrome, AFF3 expansions represent a major cause of neurodevelopmental delay.

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