Variants in the 1q21 risk region are associated with a visual endophenotype of autism and schizophrenia

Abstract

Deficits in sensitivity to visual stimuli of low spatial frequency and high temporal frequency (so-called frequency-doubled gratings) have been demonstrated both in schizophrenia and in autism spectrum disorder (ASD). Such basic perceptual functions are ideal candidates for molecular genetic study, because the underlying neural mechanisms are well characterized; but they have sometimes been overlooked in favor of cognitive and neurophysiological endophenotypes, for which neural substrates are often unknown. Here, we report a genome-wide association study of a basic visual endophenotype associated with psychological disorder. Sensitivity to frequency-doubled gratings was measured in 1060 healthy young adults, and analyzed for association with genotype using linear regression at 642 758 single nucleotide polymorphism (SNP) markers. A significant association (P = 7.9 × 10 −9 ) was found with the SNP marker rs1797052, situated in the 5 -untranslated region of PDZK1; each additional copy of the minor allele was associated with an increase in sensitivity equivalent to more than half a standard deviation. A permutation procedure, which accounts for multiple testing, showed that the association was significant at the α = 0.005 level. The region on chromosome 1q21.1 surrounding PDZK1 is an established susceptibility locus both for schizophrenia and for ASD, mirroring the common association of the visual endophenotype with the two disorders. PDZK1 interacts with N-methyl-Daspartate receptors and neuroligins, which have been implicated in the etiologies of schizophrenia and ASD. These findings suggest that perceptual abnormalities observed in two different disorders may be linked by common genetic elements.

PDZK1/NHERF3 Differentially Regulates Corticotropin-releasing Factor Receptor 1 and Serotonin 2A Receptor Signaling and Endocytosis

“…The interaction of PDZK1 with NMDARs and neuroligins provide additional evidence for the potential involvement of PDZK1 in mental illnesses associated with NMDAR and neuroligin signaling which have been implicated in the etiologies of autism and schizophrenia. In addition, the region on chromosome 1q21.1 surrounding PDZK1 is an established susceptibility locus both for schizophrenia and for autism spectrum disorder [59].…”

General and specific factors in the processing of faces

“…For the guidance of other researchers, we record in Table 6 the SNPs that had suggestive associations with our performance measures. Sex was entered as a covariate in all the genetic analyses (for a more detailed description of the genetic methods, see Goodbourn et al, 2014 andLawrance-Owen et al, 2013). …”

Individual differences in visual science: What can be learned and what is good experimental practice?

“…Genetic variation in DNA has been correlated with individual variation in visual perceptual and neural traits, using either a candidate-gene approach or genome-wide association (e.g. Goodbourn et al, 2014 on contrast sensitivity; Bosten et al, 2014 on phorias; Verhallen et al, 2014 on face perception; see also Mollon, 1986). New genetic methods such as pathway analysis (Torkamani, Topol, & Schork, 2008) can be similarly applied.…”