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Common Variant Associations with Fragile X Syndrome

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

Posted 11 Mar 2017
bioRxiv DOI: 10.1101/115998 (published DOI: 10.1038/s41380-018-0290-3)

Fragile X syndrome is a common cause of intellectual disability. It is usually caused by a de novo mutation which often occur on multiple haplotypes and should not be detectible using genome-wide association (GWA). We conducted GWA 89 male FXS cases and 266 male controls, and detected multiple genome-wide significant signals near FMR1 (odds ratio=8.10, P=2.5x10-10). These findings withstood robust attempts at falsification. Fine-mapping did not serve to narrow the interval (minimum P=1.13x10-14), and functional genomic integration (including 5C data we generated for this region) did not provide a mechanistic hypothesis. Controls carrying a risk haplotype had significantly longer and more variable FMR1 CGG repeats than controls with the protective haplotype (P=4.75x10-5) which may predispose toward increases in CGG number to the pre-mutation range over many generations. This is a salutary reminder of the complexity of even “simple” monogenetic disorders.

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