The role of ASTN2 variants in childhood and adult ADHD, comorbid disorders and associated personality traits

Abstract

Previous linkage and genome wide association (GWA) studies in ADHD indicated astrotactin 2 (ASTN2) as a candidate gene for attention-deficit/hyperactivity disorder (ADHD). ASTN2 plays a key role in glial-guided neuronal migration. To investigate whether common variants in ASTN2 contribute to ADHD disorder risk, we tested 63 SNPs spanning ASTN2 for association with ADHD and specific comorbid disorders in two samples: 171 families of children with ADHD and their parents (N = 592), and an adult sample comprising 604 adult ADHD cases and 974 controls. The C-allele of rs12376789 in ASTN2 nominally increased the risk for ADHD in the trio sample (p = 0.025). This was not observed in the adult case-control sample alone, but retained in the combined sample (nominal p = 0.030). Several other SNPs showed nominally significant association with comorbid disorders, especially anxiety disorder, in the childhood and adult ADHD samples. Some ASTN2 variants were nominally associated with personality traits in the adult ADHD sample and overlapped with risk alleles for comorbid disorders in childhood. None of the findings survived correction for multiple testing, thus, results do not support a major role of common variants in ASTN2 in the pathogenesis of ADHD, its comorbid disorders or ADHD associated personality traits.

Cleave but not leave: Astrotactin proteins in development and disease

“…Defects in neuronal migration can cause a number of human developmental malformations (41,42). Given the evidence from animal models that Astn1 and possibly Astn2 are required for glial-guided neuronal migration, the involvement of astrotactins in human CNS disorders has been an object of intense interest for the past decade (8)(9)(10)(11)(43)(44)(45). Several linkage studies have suggested a possible role of astrotactins in neurodevelopmental and neurodegenerative disease.…”

Whole-genome sequencing reveals the genetic mechanisms of domestication in classical inbred mice

“…It has been reported that Astn2 attended neuronal migration [67] and surface protein trafficking [68]. ASTN2 is also widely proven to be associated with a number of mental illnesses in humans [37][38][39][40][41][42][43][44][45][46][47][48][49][50][51] and has exhibited a relationship with hippocampus volume [69,70]. A previous study showed that the double knockout of the exon 5 of Astn2 and Fz6 (Frizzled6) led to a 180° hair orientation reversal on the back of mice [71]; however, no behavioral phenotype of Astn2 has yet been found in mutant or knockout mouse models.…”

“…S9), indicating the core role of behavioral modification in mice domestication. Worthy of mention is that some PSGs without known behavioral phenotypes are associated with human mental illnesses, e.g., CBLN4 (Alzheimer's disease [33]), WBSCR17 (Parkinson's disease [34,35], autism [36]), and ASTN2 (autism [37][38][39][40][41][42], Alzheimer's disease [43,44], intellectual disability [45,46], schizophrenia [47,48], and attention deficit/hyperactivity disorder [40,[49][50][51]).…”

Effects of rs958804 and rs7858836 single‐nucleotide polymorphisms of the ASTN2 gene on pain‐related phenotypes in patients who underwent laparoscopic colectomy and mandibular sagittal split ramus osteotomy

“…Together with astrotactin 1, astrotactin 2 plays a key role in glial‐guided neuronal migration during development of the laminar architecture of cortical regions of the mammalian brain 23,24 . Some researchers reported that certain variants of the ASTN2 gene might be associated with the development of neuropsychiatric disorders, such as autism spectrum disorder, attention‐deficit/hyperactivity disorder, anxiety, obsessive‐compulsive disorder, schizophrenia, and Alzheimer's disease, 25–27 although others did not find such associations between ASTN2 gene variants and neuropsychiatric disorders 28 . A substantial number of studies have shown or suggested interactions between these neuropsychiatric disorders and alterations of opioid system function 29–32 .…”