Title: Common-variant associations with fragile X syndrome.

Authors: Crowley, James J; Szatkiewicz, Jin; Kähler, Anna K; Giusti-Rodriguez, Paola; Ancalade, NaEshia; Booker, Jessica K; Carr, Jennifer L; Crawford, Greg E; Losh, Molly; Stockmeier, Craig A; Taylor, Annette K; Piven, Joseph; Sullivan, Patrick F

Published In Mol Psychiatry, (2019 03)

Abstract: Fragile X syndrome is rare but a prominent cause of intellectual disability. It is usually caused by a de novo mutation that occurs on multiple haplotypes and thus would not be expected to be detectible using genome-wide association (GWA). We conducted GWA in 89 male FXS cases and 266 male controls, and detected multiple genome-wide significant signals near FMR1 (odds ratio = 8.10, P = 2.5 × 10-10). These findings withstood robust attempts at falsification. Fine-mapping yielded a minimum P = 1.13 × 10-14, but did not narrow the interval. Comprehensive functional genomic integration did not provide a mechanistic hypothesis. Controls carrying a risk haplotype had significantly longer FMR1 CGG repeats than controls with the protective haplotype (P = 4.75 × 10-5), which may predispose toward increases in CGG number to the premutation range over many generations. This is a salutary reminder of the complexity of even "simple" monogenetic disorders.

PubMed ID: 30531935

MeSH Terms: Adult; Fragile X Mental Retardation Protein/genetics*; Fragile X Mental Retardation Protein/metabolism; Fragile X Syndrome/genetics*; Genetic Predisposition to Disease/genetics; Genome-Wide Association Study; Haplotypes/genetics; Humans; Intellectual Disability/genetics; Male; Mutation; Risk Factors