A rare WNT1 missense variant overrepresented in ASD leads to increased Wnt signal pathway activation

P-M Martin,J Quinn,R T Moon,N Robin,X Yang,S P Hamilton,P-Y Kwok,B N R Cheyette,L A Weiss,E Lam,C A Erdman,J S Rabinowitz

doi:10.1038/tp.2013.75

Abstract

Wnt signaling, which encompasses multiple biochemical pathways that regulate neural development downstream of extracellular Wnt glycoprotein ligands, has been suggested to contribute to major psychiatric disorders including autism spectrum disorders (ASD). We used next-generation sequencing and Sequenom genotyping technologies to resequence 10 Wnt signaling pathway genes in 198 ASD patients and 240 matched controls. Results for single-nucleotide polymorphisms (SNPs) of interest were confirmed in a second set of 91 ASD and 144 control samples. We found a significantly increased burden of extremely rare missense variants predicted to be deleterious by PolyPhen-2, distributed across seven genes in the ASD sample (3.5% in ASD vs 0.8% in controls; Fisher's exact test, odds ratio (OR)=4.37, P=0.04). We also found a missense variant in WNT1 (S88R) that was overrepresented in the ASD sample (8 A/T in 267 ASD (minor allele frequency (MAF)=1.69%) vs 1 A/T in 377 controls (MAF=0.13%), OR=13.0, Fisher's exact test, P=0.0048; OR=8.2 and P=0.053 after correction for population stratification). Functional analysis revealed that WNT1-S88R is more active than wild-type WNT1 in assays for the Wnt/β-catenin signaling pathway. Our findings of a higher burden in ASD of rare missense variants distributed across 7 of 10 Wnt signaling pathway genes tested, and of a functional variant at the WNT1 locus associated with ASD, support that dysfunction of this pathway contributes to ASD susceptibility. Given recent findings of common molecular mechanisms in ASD, schizophrenia and affective disorders, these loci merit scrutiny in other psychiatric conditions as well.

Highlights

Autism spectrum disorders (ASD) have a strong genetic etiology
Our finding in ASD of a higher burden of rare missense variants distributed across 7 of 10 Wnt signaling pathway genes tested, and of an ASD-associated functional variant at the WNT1 locus, supports that dysfunction of this pathway contributes to ASD susceptibility
In functional assays for the Wnt/b-catenin pathway, the biochemical cascade physiologically activated by the WNT1 gene product,[40,41] WNT1-S88R consistently showed increased activity

Summary

Introduction

Autism spectrum disorders (ASD) have a strong genetic etiology. The last decade of research in psychiatric genetics has led to groundbreaking discoveries, including the identification of ASD-associated sequence and structural variants in a variety of genes implicated in brain development— in synapse formation, maintenance and function. Wnt signaling influences subdivision of the anterior neural tube into major brain regions (such as forebrain, midbrain and hindbrain), neural precursor proliferation, neural cell fate and migration, axon guidance, dendrite development and synapse formation.[1] Given this broad spectrum of roles, it is no surprise that dysregulation of Wnt signaling causes a broad spectrum of deleterious effects on neural development, and largely on this basis it has long been considered a candidate pathway in psychiatric pathogenesis Its candidacy in this regard is supported by evidence that Wnt signaling pathway components are pharmacological targets of lithium,[2,3] hallucinogenic drugs 4 and antipsychotic medications,[5,6] as well as by evidence derived from behavioral tests in animal models[7,8,9,10,11] and from positive associations in scattered human genetic studies.[12,13,14,15,16,17]

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Results

Conclusion