Common-variant associations with fragile X syndrome.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Crowley, JJ; Szatkiewicz, J; Kähler, AK; Giusti-Rodriguez, P; Ancalade, N; Booker, JK; Carr, JL; Crawford, GE; Losh, M; Stockmeier, CA; Taylor, AK; Piven, J; Sullivan, PF

Published Date

  • March 2019

Published In

Volume / Issue

  • 24 / 3

Start / End Page

  • 338 - 344

PubMed ID

  • 30531935

Pubmed Central ID

  • PMC6457435

Electronic International Standard Serial Number (EISSN)

  • 1476-5578

Digital Object Identifier (DOI)

  • 10.1038/s41380-018-0290-3


  • eng

Conference Location

  • England