Common-variant associations with fragile X syndrome

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,...

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Bibliographic Details
Published in:Molecular psychiatry 2019-03, Vol.24 (3), p.338-344
Main Authors: Crowley, James J., Szatkiewicz, Jin, Kähler, Anna K., Giusti-Rodriguez, Paola, Ancalade, NaEshia, Booker, Jessica K., Carr, Jennifer L., Crawford, Greg E., Losh, Molly, Stockmeier, Craig A., Taylor, Annette K., Piven, Joseph, Sullivan, Patrick F.
Format: Article
Language:English
Subjects:
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631/208
692/699/476/1373
Adult
Behavioral Sciences
Biological Psychology
Chromosomes
FMR1 protein
Fragile X Mental Retardation Protein - genetics
Fragile X Mental Retardation Protein - metabolism
Fragile X syndrome
Fragile X Syndrome - genetics
Gene mapping
Gene mutation
Genetic aspects
Genetic Predisposition to Disease - genetics
Genome-Wide Association Study
Genomes
Genomics
Haplotypes
Haplotypes - genetics
Humans
Immediate Communication
Intellectual disabilities
Intellectual Disability - genetics
Male
Medicin och hälsovetenskap
Medicine
Medicine & Public Health
Mutation
Neurosciences
Pharmacotherapy
Psychiatry
Risk Factors
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Summary: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.
ISSN:1359-4184
1476-5578
1476-5578
DOI:10.1038/s41380-018-0290-3