MACROD2 gene associated with autistic-like traits in a general population sample

Abstract

There is now substantial evidence that autistic-like traits in the general population lie on a continuum, with clinical autism spectrum disorders (ASD) representing the extreme end of this distribution. In this study, we sought to evaluate five independently identified genetic associations with ASD with autistic-like traits in the general population. In the study cohort, clinical phenotype and genomewide association genotype data were obtained from the Western Australian Pregnancy Cohort (Raine) Study. The outcome measure used was the Autism Spectrum Quotient (AQ), a quantitative measure of autistic-like traits of individuals in the cohort. Total AQ scores were calculated for each individual, as well as scores for three subscales. Five candidate single nucleotide polymorphism (SNP) associations with ASD, reported in previously published genomewide association studies, were selected using a nominal cutoff value of P less than 1.0 × 10−5. We tested whether these five SNPs were associated with total AQ and the subscales, after adjustment for possible confounders. SNP rs4141463 located in the macro domain containing 2 (MACROD2) gene was significantly associated with the Communication/Mindreading subscale. No other SNP was significantly associated with total AQ or the subscales. The MACROD2 gene is a strong positional candidate risk factor for autistic-like traits in the general population.

ATM induces MacroD2 nuclear export upon DNA damage

“…The TARG1 sequence consists only of a macrodomain, but MacroD2 is twice the size of TARG1, containing a C-terminal region as long as the macrodomain itself. Although the exact molecular functions of MacroD2 are unknown, it has been associated with cancer and neurological disorders (21–27). …”

A Genome Wide Copy Number Variations Analysis in Autism Spectrum Disorder (Asd) and Intellectual Disability (Id) in Italian Families

“…This gene is a strong positional candidate risk factor for autistic-like traits in the general population [14]. A maternally inherited duplication of band 9q22 was found in an ID case.…”

“…We identified the following rearrangements: a duplication of NPHP1 gene in 2q13 [8]; a de novo 7q32.3 gain involving PLXNA4 [9]; a 9p24.3 duplication involving KANK1 gene [10]; a duplication of PTCH1 in 9q22 [11]; a 5.8 Mb deletion on 12p12.2p12.1 including SOX5 [12]; a duplication of the 16q24.2 region [13]; an inherited 20p12.1 deletion interrupting the MACROD2 gene [14]; a Xp11.22 duplication involving KDM5C and IQSEC2 [15]; a duplication in Xp22.12 including the RPS6KA3 gene [16]; and the deletion of PTCHD1 in Xp22.11 [17]. …”

Genetic Investigation of Autism-Related Social Communication Deficits

“…Two of these loci are also associated with quantitative social communication phenotypes in large general population samples (18,19), indicating that multiple genes contribute to autism-related endophenotypes. Biological studies have revealed that the functional element at one of these genome-wide significant loci (13,19) is a gene encoding a regulatory, long noncoding RNA, MSNP1AS, suggesting that we will need to look beyond the exome-the 2% of the human genome that encodes proteins-to identify Rare variants may contribute to the autismrelated social responsiveness phenotype.…”