Variants in TTC25 affect autistic trait in patients with autism spectrum disorder and general population

Abstract

Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder with a complex genetic architecture. To identify genetic variants underlying ASD, we performed single-variant and gene-based genome-wide association studies using a dense genotyping array containing over 2.3 million single-nucleotide variants in a discovery sample of 160 families with at least one child affected with non-syndromic ASD using a binary (ASD yes/no) phenotype and a quantitative autistic trait. Replication of the top findings was performed in Psychiatric Genomics Consortium and Erasmus Rucphen Family (ERF) cohort study. Significant association of quantitative autistic trait was observed with the TTC25 gene at 17q21.2 (effect size=10.2, P-value=3.4 × 10) in the gene-based analysis. The gene also showed nominally significant association in the cohort-based ERF study (effect=1.75, P-value=0.05). Meta-analysis of discovery and replication improved the association signal (P-value=1.5 × 10). No genome-wide significant signal was observed in the single-variant analysis of either the binary ASD phenotype or the quantitative autistic trait. Our study has identified a novel gene TTC25 to be associated with quantitative autistic trait in patients with ASD. The replication of association in a cohort-based study and the effect estimate suggest that variants in TTC25 may also be relevant for broader ASD phenotype in the general population. TTC25 is overexpressed in frontal cortex and testis and is known to be involved in cilium movement and thus an interesting candidate gene for autistic trait.

A cryptic microdeletion del(12)(p11.21p11.23) within an unbalanced translocation t(7;12)(q21.13;q23.1) implicates new candidate loci for intellectual disability and Kallmann syndrome

“…On the other hand, a de novo missense variant in TMTC1 (TransMembrane and Tetratricopeptide repeat Containing 1, MIM 615855) was found in a child with NDD 27 . The Tetratricopeptide repeat (TPR) structural motif present in TMTC1 is also found in other genes such as NAA15 66 , OGT [67][68][69] , TANC2 70 , and TTC25 71 , all of which are associated with autism and ID. TMTC1 interacts with BCOR (BCL6 Corepressor, 300485) 72 and VIRMA (Vir like M6A Methyltransferase Associated, MIM 616447) (aka KIAA1429) 73 .…”

Genome‐wide association analysis of autism identified multiple loci that have been reported as strong signals for neuropsychiatric disorders

“…The combined P ‐value was calculated for SNPs common to both genotyping platforms and showing consistent association signal at a nominal level using Stouffer's z ‐score method. The European ancestry data included one in Swedish from iPSYCH and PGC‐ASD GWAS [Vojinovic et al, ], downloaded from the PCG website (http://www.med.unc.edu/pgc). The iPSYCH, including 13,076 cases and 22,664 controls, was comprised of five family‐based data sets of European ancestry; the PCG data set contains the result of 5,305 cases and 5,305 controls individual SNPs for association results for ASD that is based on pseudo‐case–control.…”