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

doi:10.1038/s41380-018-0290-3

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

Communication Sciences and Disorders

Research output: Contribution to journal › Article

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.

Original language	English (US)
Pages (from-to)	338-344
Number of pages	7
Journal	Molecular Psychiatry
Volume	24
Issue number	3
DOIs	https://doi.org/10.1038/s41380-018-0290-3
State	Published - Mar 1 2019

ASJC Scopus subject areas

Molecular Biology
Psychiatry and Mental health
Cellular and Molecular Neuroscience

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Crowley, J. J., Szatkiewicz, J., Kähler, A. K., Giusti-Rodriguez, P., Ancalade, N. E., Booker, J. K., Carr, J. L., Crawford, G. E., Losh, M., Stockmeier, C. A., Taylor, A. K., Piven, J., & Sullivan, P. F. (2019). Common-variant associations with fragile X syndrome. Molecular Psychiatry, 24(3), 338-344. https://doi.org/10.1038/s41380-018-0290-3

Crowley, James J. ; Szatkiewicz, Jin ; Kähler, Anna K. ; Giusti-Rodriguez, Paola ; Ancalade, Na Eshia ; Booker, Jessica K. ; Carr, Jennifer L. ; Crawford, Greg E. ; Losh, Molly ; Stockmeier, Craig A. ; Taylor, Annette K. ; Piven, Joseph ; Sullivan, Patrick F. / Common-variant associations with fragile X syndrome. In: Molecular Psychiatry. 2019 ; Vol. 24, No. 3. pp. 338-344.

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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. ",

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Common-variant associations with fragile X syndrome. / Crowley, James J.; Szatkiewicz, Jin; Kähler, Anna K.; Giusti-Rodriguez, Paola; Ancalade, Na Eshia; Booker, Jessica K.; Carr, Jennifer L.; Crawford, Greg E.; Losh, Molly; Stockmeier, Craig A.; Taylor, Annette K.; Piven, Joseph; Sullivan, Patrick F.

In: Molecular Psychiatry, Vol. 24, No. 3, 01.03.2019, p. 338-344.

Research output: Contribution to journal › Article

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