A noise-reduction GWAS analysis implicates altered regulation of neurite outgrowth and guidance in autism

Abstract

BackgroundGenome-wide Association Studies (GWAS) have proved invaluable for the identification of disease susceptibility genes. However, the prioritization of candidate genes and regions for follow-up studies often proves difficult due to false-positive associations caused by statistical noise and multiple-testing. In order to address this issue, we propose the novel GWAS noise reduction (GWAS-NR) method as a way to increase the power to detect true associations in GWAS, particularly in complex diseases such as autism.MethodsGWAS-NR utilizes a linear filter to identify genomic regions demonstrating correlation among association signals in multiple datasets. We used computer simulations to assess the ability of GWAS-NR to detect association against the commonly used joint analysis and Fisher's methods. Furthermore, we applied GWAS-NR to a family-based autism GWAS of 597 families and a second existing autism GWAS of 696 families from the Autism Genetic Resource Exchange (AGRE) to arrive at a compendium of autism candidate genes. These genes were manually annotated and classified by a literature review and functional grouping in order to reveal biological pathways which might contribute to autism aetiology.ResultsComputer simulations indicate that GWAS-NR achieves a significantly higher classification rate for true positive association signals than either the joint analysis or Fisher's methods and that it can also achieve this when there is imperfect marker overlap across datasets or when the closest disease-related polymorphism is not directly typed. In two autism datasets, GWAS-NR analysis resulted in 1535 significant linkage disequilibrium (LD) blocks overlapping 431 unique reference sequencing (RefSeq) genes. Moreover, we identified the nearest RefSeq gene to the non-gene overlapping LD blocks, producing a final candidate set of 860 genes. Functional categorization of these implicated genes indicates that a significant proportion of them cooperate in a coherent pathway that regulates the directional protrusion of axons and dendrites to their appropriate synaptic targets.ConclusionsAs statistical noise is likely to particularly affect studies of complex disorders, where genetic heterogeneity or interaction between genes may confound the ability to detect association, GWAS-NR offers a powerful method for prioritizing regions for follow-up studies. Applying this method to autism datasets, GWAS-NR analysis indicates that a large subset of genes involved in the outgrowth and guidance of axons and dendrites is implicated in the aetiology of autism.

RIM-binding protein 2 regulates release probability by fine-tuning calcium channel localization at murine hippocampal synapses

“…A larger distance between Ca V 2.1s and release sites would result in an altered local Ca 2+ profile "seen" by the Ca 2+ sensor for release, which determines vesicle fusion and strongly depends on the coupling distance (17). RIM-BPs have been identified in a number of studies as candidate genes for autism spectrum disorder (ASD) (18)(19)(20)(21). Although neurons might be able to compensate for the 10% decrease in P VR by homeostatic mechanisms, it is likely that the robust changes in STP might ultimately severely alter the computational properties and function of the affected neuronal networks, and thereby perturb synaptic information processing (22).…”

Autism throughout genetics: Perusal of the implication of ion channels

“…Another α 1 subunit of the T‐type calcium channel‐encoding gene ( CACNA1G ) mapped at 17q11–q21 region was found to contain SNPs (rs12603122, rs757415, rs12603112, and rs198547) in patients with ASD (Lu, Dai, Martinez‐Agosto, & Cantor, 2012). A statistical re‐analysis of a GWAS data of patients with ASD from the AGRE revealed the association of the CACNA1I gene encoding for Ca V 3.3 of Ca 2+ channel in ASD (Hussman et al., 2011). Yatsenko et al.…”

Neurodevelopmental Perspectives on Wnt Signaling in Psychiatry

“…The development of functional neural circuits governing thought and behavior relies in large measure on precisely guided outgrowth and pathfinding of axons to reach specific target cells. On this basis, dysregulated axon guidance is a candidate neurodevelopmental mechanism that could conceptually contribute to a wide range of behavioral disorders [146,147,148,149,150,151]. …”