Contribution of common and rare variants of the PTCHD1 gene to autism spectrum disorders and intellectual disability

Abstract

Recent findings revealed rare copy number variants and missense changes in the X-linked gene PTCHD1 in autism spectrum disorder (ASD) and intellectual disability (ID). Here, we aim to explore the contribution of common PTCHD1 variants in ASD and gain additional evidence for the role of rare variants of this gene in ASD and ID. A two-stage case-control association study investigated 28 tag single nucleotide polymorphisms (SNPs) in 994 ASD cases and 1035 controls from four European populations. Mutation screening was performed in 673 individuals who included 240 ASD cases, 183 ID patients and 250 controls. The case-control association study showed a significant association with rs7052177 (P = 6.13E-4) in the ASD discovery sample that was replicated in an independent sample (P = 0.03). A Mantel-Haenszel meta-analysis for rs7052177T considering the four European populations showed an odds ratio of 0.58 (P = 7E-05). This SNP is predicted to be located in a transcription factor binding site. No rare missense PTCHD1 variants were found in our ASD cohort and only one was identified in the ID sample. A duplication (27 bp) in the promoter region, absent from 590 controls, was found in three ASD patients (Fisher exact test, P = 0.024). A gene reporter assay showed a significant decrease in the transcriptional activity (26%) driven by this variant. Moreover, we found that the longest allele of a trinucleotide repeat located upstream from PTCHD1 was associated with ASD (P = 0.003, permP = 0.0186). Our results further support the involvement of PTCHD1 in ASD, suggesting that both common and rare variants contribute to the disorder. INTRODUCTIONAutism spectrum disorder (ASD) is a severe neurodevelopmental disorder characterized by impairments in reciprocal social interaction, verbal and non-verbal communication and stereotyped patterns of behavior. The prevalence for ASD is estimated to be about 0.5-1%, and it is approximately four times more frequent in males than in females. [1][2][3] Family and twin studies in recent decades have provided strong evidence showing that ASD is one of the most heritable neuropsychiatric disorders. Sibling recurrence risk is approximately 20%, and concordance among twins may range from 76 to 88% for monozygotic twins and from 0 to 31% for dizygotic twins, depending on phenotypic criteria. 4,5 The genetic model for idiopathic autism is complex. Recent studies suggest that at least 1000 genes contribute to the disorder, with a combination of common variants of small to moderate effect and rare variants with potential larger effect sizes. 6,7

Genome-wide Association Study Identifies a Regulatory Variant of RGMA Associated With Opioid Dependence in European Americans

“…These genes are GRIN1 (glutamate receptor, ionotropic, N-methyl D-aspartate 1), KCNIP3 (Kv channel interacting protein 3, calsenilin), PTCHD1 (patched domain containing 1), FXYD6 (FXYD domain containing ion transport regulator 6), DLG4 (discs, large homolog 4) and NRG1 (neuregulin 1), as well as two potential regulators ( TCF3 and TCF4 ). GRIN1 , FXYD6 , NRG1 and DLG4 have been associated with schizophrenia (21-24), KCNIP3 with Alzheimer's disease (25), PTCHD1 with autism (26), and NRG1 with psychosis (27). The E-box (5′-CANNTG-3′) motif of the two potential regulators, TCF3 and TCF4 , was found in the promoter region of RGMA , GRIN1 and PTCHD1 .…”

“…C57BL/6J mice have a greater preference for oral self-administration of morphine than three other strains (19). Further co-expression analysis in large brain tissue expression datasets demonstrated significant correlation between the expression of RGMA and that of four genes that have been shown to affect risk for other psychiatric disorders, GRIN1 (schizophrenia) (23), KCNIP3 (Alzheimer's disease) (25), FXYD6 (schizophrenia) (21) and PTCHD1 (autism) (26), as well as two transcription factors TCF3 and TCF4 . The latter gene TCF4 is a schizophrenia-risk gene (28).…”

“…The overexpression of GRIN1 increases the amount of μ-opioid receptor in lipid rafts and the magnitude of receptor signaling. The significant correlation between the expression of other genes ( PTCHD1 , FXYD6 , and KCNIP3 ) and that of RGMA , may reflect their critical function in the brain (21, 26, 41). These findings raise the question of whether, in response to opioid stimulation in brain, there is crosstalk between RGMA and GRIN1 , and possibly KCNIP3 , FXYD6 and PTCHD1 as well.…”

Truncating Variant Burden in High Functioning Autism and Pleiotropic Effects ofLRP1Across Psychiatric Phenotypes

“…From our collection of ASD families (54, 55), we selected 20 singleton Spanish families without any other psychiatric history amongst relatives. All probands had high functioning autism (HFA), which defined as having full scale IQ greater than 70 (IQ average = 100, SD±14.7, range 80–135).…”

Lack of replication of previous autism spectrum disorder GWAS hits in European populations

“…All ASD patients met ICD‐10 or DSM‐IV TR criteria for autism, Asperger disorder or pervasive developmental disorder not otherwise specified (PDD‐NOS), assessed using ADI‐R (Autism‐Diagnostic Interview‐Revised) [Lord, Rutter, & Le Couteur, ] and when possible also ADOS (Autism Diagnostic Observation Schedule) [Lord et al, ]. Additional information about case and control samples for each country regarding recruitment, diagnostic approach and selection can be found in previous publications [Bacchelli et al, ; Mosca‐Boidron et al, ; Prandini et al, ; Toma et al, ; Torrico et al, ; van Steijn et al, ; Waltes et al, ]. In this study, ASD patients were considered high functioning if their IQ score was greater than 70.…”