A Genome-Wide Survey of Transgenerational Genetic Effects in Autism

Kathryn M Tsang,Gerald N Delorenze,Lauren A Weiss,Gayle C Windham,Cathleen K Yoshida,Ousseny Zerbo,Lisa A Croen,Anthony R Torres,Martin Kharrazi,Michael Edward Zwick

doi:10.1371/journal.pone.0076978

Abstract

Effects of parental genotype or parent-offspring genetic interaction are well established in model organisms for a variety of traits. However, these transgenerational genetic models are rarely studied in humans. We have utilized an autism case-control study with 735 mother-child pairs to perform genome-wide screening for maternal genetic effects and maternal-offspring genetic interaction. We used simple models of single locus parent-child interaction and identified suggestive results (P<10−4) that cannot be explained by main effects, but no genome-wide significant signals. Some of these maternal and maternal-child associations were in or adjacent to autism candidate genes including: PCDH9, FOXP1, GABRB3, NRXN1, RELN, MACROD2, FHIT, RORA, CNTN4, CNTNAP2, FAM135B, LAMA1, NFIA, NLGN4X, RAPGEF4, and SDK1. We attempted validation of potential autism association under maternal-specific models using maternal-paternal comparison in family-based GWAS datasets. Our results suggest that further study of parental genetic effects and parent-child interaction in autism is warranted.

Highlights

Autism is a heterogeneous neurodevelopmental disorder defined by deficits in language and social behavior as well as patterns of repetitive behaviors
Children with autism spectrum disorder (ASD) or DD were ascertained from client records of the Regional Center of Orange County (RCOC), and San Diego Regional Center, two of the 21 Regional Centers operated by the California Department of Developmental Services (DDS) to coordinate services for persons with autism, developmental delay, and other developmental disabilities
To separate maternal main effects from proband main effects, we carried out a comparison between multinomial maximum likelihood models (MMLMs) including both maternal and proband main effects and only proband main effects using a likelihood ratio test (LRT)

Summary

Introduction

Autism is a heterogeneous neurodevelopmental disorder defined by deficits in language and social behavior as well as patterns of repetitive behaviors. While familybased studies suggest that the inheritance of autism is complex, the occurrence of autism or autistic traits in individuals with diseases of known genetic etiology (such as Fragile X, Rett or Timothy syndrome) suggests a simpler genetic basis for autism in around 5% of autism cases [5]. The advent of more frequent and higher resolution clinical cytogenetic testing has shown that genetic copy number variation or other aberrations can be found in 10– 20% of individuals with autism, further implicating a highly penetrant genetic basis in some cases not associated with a known genetic disorder [5]. Several genome-wide association studies of common single nucleotide polymorphisms (SNPs) have been performed, but the most significant results from these studies, much like other common complex diseases, show modest effect size [6,7,8]. The genetic etiology of the majority of autism cases remains elusive

Methods

Results

Conclusion