Common-variant associations with fragile X syndrome

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)338-344
Number of pages7
JournalMolecular Psychiatry
Issue number3
StatePublished - Mar 1 2019

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Molecular Biology


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