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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This project was funded by an Autism Speaks award to PFS. PFS gratefully acknowledges support from the Swedish Research Council (Vetenskapsrådet, award D0886501). We are indebted to Dr. Mark Daly for discussions regarding the results, and to senior FXS researchers for comments after this paper appeared on bioRxiv. For the human postmortem samples, the authors acknowledge the Cuyahoga County Medical Examiner’s Office and the families of the deceased. They also note contributions of Drs. James Overholser and George Jurjus and of Lesa Dieter in the retrospective psychiatric assessments, and Dr. Grazyna Rajkowska and Gouri Mahajan in sample preparation—this work was supported by NIH/NIGMS COBRE Center for Psychiatric Neuroscience (P30 GM103328).
Conflict of interest
PFS is a scientific advisor for Lundbeck.
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Crowley, J.J., Szatkiewicz, J., Kähler, A.K. et al. Common-variant associations with fragile X syndrome. Mol Psychiatry 24, 338–344 (2019). https://doi.org/10.1038/s41380-018-0290-3