Common Variant Associations with Fragile X Syndrome

Crowley, J.; Szatkiewicz, J.; Kahler, A.; Giusti-Rodriguez, P.; Ancalade, N.; Booker, J.; Carr, J.; Crawford, G.; Losh, M.; Stockmeier, C.; Taylor, A.; Piven, J.; Sullivan, P. F.

doi:10.1101/115998

bioRxiv · 10.1101/115998

Common Variant Associations with Fragile X Syndrome

Crowley, J.·Szatkiewicz, J.·Kahler, A.·Giusti-Rodriguez, P.·Ancalade, N.·Booker, J.·Carr, J.·Crawford, G.·Losh, M.·Stockmeier, C.·Taylor, A.·Piven, J.·Sullivan, P. F.

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Abstract

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=1.13xl0-14), 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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Crowley, J., Szatkiewicz, J., Kahler, A., Giusti-Rodriguez, P., Ancalade, N., Booker, J., Carr, J., Crawford, G., Losh, M., Stockmeier, C., Taylor, A., Piven, J., Sullivan, P. F.. 2017-03-11. Common Variant Associations with Fragile X Syndrome. https://doi.org/10.1101/115998

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