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Common-variant associations with fragile X syndrome.

Publication ,  Journal Article
Crowley, JJ; Szatkiewicz, J; Kähler, AK; Giusti-Rodriguez, P; Ancalade, N; Booker, JK; Carr, JL; Crawford, GE; Losh, M; Stockmeier, CA ...
Published in: Mol Psychiatry
March 2019

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.

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Published In

Mol Psychiatry

DOI

EISSN

1476-5578

Publication Date

March 2019

Volume

24

Issue

3

Start / End Page

338 / 344

Location

England

Related Subject Headings

  • Risk Factors
  • Psychiatry
  • Mutation
  • Male
  • Intellectual Disability
  • Humans
  • Haplotypes
  • Genome-Wide Association Study
  • Genetic Predisposition to Disease
  • Fragile X Syndrome
 

Citation

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Crowley, J. J., Szatkiewicz, J., Kähler, A. K., Giusti-Rodriguez, P., Ancalade, N., Booker, J. K., … Sullivan, P. F. (2019). Common-variant associations with fragile X syndrome. Mol Psychiatry, 24(3), 338–344. https://doi.org/10.1038/s41380-018-0290-3
Crowley, James J., Jin Szatkiewicz, Anna K. Kähler, Paola Giusti-Rodriguez, NaEshia Ancalade, Jessica K. Booker, Jennifer L. Carr, et al. “Common-variant associations with fragile X syndrome.Mol Psychiatry 24, no. 3 (March 2019): 338–44. https://doi.org/10.1038/s41380-018-0290-3.
Crowley JJ, Szatkiewicz J, Kähler AK, Giusti-Rodriguez P, Ancalade N, Booker JK, et al. Common-variant associations with fragile X syndrome. Mol Psychiatry. 2019 Mar;24(3):338–44.
Crowley, James J., et al. “Common-variant associations with fragile X syndrome.Mol Psychiatry, vol. 24, no. 3, Mar. 2019, pp. 338–44. Pubmed, doi:10.1038/s41380-018-0290-3.
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. Common-variant associations with fragile X syndrome. Mol Psychiatry. 2019 Mar;24(3):338–344.

Published In

Mol Psychiatry

DOI

EISSN

1476-5578

Publication Date

March 2019

Volume

24

Issue

3

Start / End Page

338 / 344

Location

England

Related Subject Headings

  • Risk Factors
  • Psychiatry
  • Mutation
  • Male
  • Intellectual Disability
  • Humans
  • Haplotypes
  • Genome-Wide Association Study
  • Genetic Predisposition to Disease
  • Fragile X Syndrome