Common-variant associations with fragile X syndrome

  • A Correction to this article was published on 23 September 2019

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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Change history

  • 23 September 2019

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

References

  1. 1.

    Bhakar AL, Dolen G, Bear MF. The pathophysiology of fragile X (and what it teaches us about synapses). Annu Rev Neurosci. 2012;35:417–43.

    CAS  Article  Google Scholar 

  2. 2.

    Turner G, Webb T, Wake S, Robinson H. Prevalence of fragile X syndrome. Am J Med Genet. 1996;64:196–7.

    CAS  Article  Google Scholar 

  3. 3.

    Sherman SL. Epidemiology. In: Hagerman R, Hagerman P, editors. Fragile X Syndrome: Diagnosis, Treatment and Research. Baltimore: The Johns Hopkins University Press; 2002. p. 136–68.

    Google Scholar 

  4. 4.

    Terracciano A, Chiurazzi P, Neri G. Fragile X syndrome. Am J Med Genet C Semin Med Genet. 2005;137:32–7.

    Article  Google Scholar 

  5. 5.

    Oberle I, et al. Instability of a 550-base pair DNA segment and abnormal methylation in fragile X syndrome. Science. 1991;252:1097–102.

    CAS  Article  Google Scholar 

  6. 6.

    Verkerk AJ, et al. Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell. 1991;65:905–14.

    CAS  Article  Google Scholar 

  7. 7.

    Yu S, et al. Fragile X genotype characterized by an unstable region of DNA. Science. 1991;252:1179–81.

    CAS  Article  Google Scholar 

  8. 8.

    Jin P, Alisch RS, Warren ST. RNA and microRNAs in fragile X mental retardation. Nat Cell Biol. 2004;6:1048–53.

    CAS  Article  Google Scholar 

  9. 9.

    Veltman JA, Brunner HG. De novo mutations in human genetic disease. Nat Rev Genet. 2012;13:565–75.

    CAS  Article  Google Scholar 

  10. 10.

    Lek M, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536:285–91.

    Article  Google Scholar 

  11. 11.

    Ripke S, et al. Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nat Genet. 2013;45:1150–9.

    CAS  Article  Google Scholar 

  12. 12.

    Ripke S, et al. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511:421–7.

    Article  Google Scholar 

  13. 13.

    Altshuler DM, et al. Integrating common and rare genetic variation in diverse human populations. Nature. 2010;467:52–8.

    CAS  Article  Google Scholar 

  14. 14.

    Taylor AK, et al. Molecular predictors of cognitive involvement in female carriers of fragile X syndrome. J Am Med Assoc. 1994;271:507–14.

    CAS  Article  Google Scholar 

  15. 15.

    Merenstein SA, et al. Molecular-clinical correlations in males with an expanded FMR1 mutation. Am J Med Genet. 1996;64:388–94.

    CAS  Article  Google Scholar 

  16. 16.

    Loesch DZ, Huggins RM, Bui QM, Taylor AK, Hagerman RJ. Relationship of deficits of FMR1 gene specific protein with physical phenotype of fragile X males and females in pedigrees: a new perspective. Am J Med Genet A. 2003;118:127–34.

    Article  Google Scholar 

  17. 17.

    Chang CC, et al. Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience. 2015;4:7.

    Article  Google Scholar 

  18. 18.

    Gerhardt J, et al. Cis-acting DNA sequence at a replication origin promotes repeat expansion to fragile X full mutation. J Cell Biol. 2014;206:599–607.

    CAS  Article  Google Scholar 

  19. 19.

    Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005;21:263–5.

    CAS  Article  Google Scholar 

  20. 20.

    Price AL, et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet. 2006;38:904–9.

    CAS  Article  Google Scholar 

  21. 21.

    Hindorff LA, et al. Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc Natl Acad Sci USA. 2009;106:9362–7.

    CAS  Article  Google Scholar 

  22. 22.

    Fromer M, et al. Gene expression elucidates functional impact of polygenic risk for schizophrenia. Nat Neurosci. 2016;19:1442–53.

    CAS  Article  Google Scholar 

  23. 23.

    Giusti-Rodríguez, P. et al. Schizophrenia and a high-resolution map of the three-dimensional chromatin interactome of adult and fetal cortex. 2018 [submitted for publication].

  24. 24.

    Peltonen L, Jalanko A, Varilo T. Molecular genetics of the Finnish disease heritage. Hum Mol Genet. 1999;8:1913–23.

    CAS  Article  Google Scholar 

  25. 25.

    Struewing JP, et al. The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med. 1997;336:1401–8.

    CAS  Article  Google Scholar 

  26. 26.

    Anderson CA, Soranzo N, Zeggini E, Barrett JC. Synthetic associations are unlikely to account for many common disease genome-wide association signals. PLoS Biol. 2011;9:e1000580.

    CAS  Article  Google Scholar 

  27. 27.

    Berg IL, et al. PRDM9 variation strongly influences recombination hot-spot activity and meiotic instability in humans. Nat Genet. 2010;42:859–63.

    CAS  Article  Google Scholar 

  28. 28.

    Hastings PJ, Lupski JR, Rosenberg SM, Ira G. Mechanisms of change in gene copy number. Nat Rev Genet. 2009;10:551–64.

    CAS  Article  Google Scholar 

  29. 29.

    Koren A, et al. Differential relationship of DNA replication timing to different forms of human mutation and variation. Am J Hum Genet. 2012;91:1033–40.

    CAS  Article  Google Scholar 

  30. 30.

    Libby RT, et al. CTCF cis-regulates trinucleotide repeat instability in an epigenetic manner: a novel basis for mutational hot spot determination. PLoS Genet. 2008;4:e1000257.

    Article  Google Scholar 

  31. 31.

    Brock GJ, Anderson NH, Monckton DG. Cis-acting modifiers of expanded CAG/CTG triplet repeat expandability: associations with flanking GC content and proximity to CpG islands. Hum Mol Genet. 1999;8:1061–7.

    CAS  Article  Google Scholar 

  32. 32.

    Eichler EE, et al. Length of uninterrupted CGG repeats determines instability in the FMR1 gene. Nat Genet. 1994;8:88–94.

    CAS  Article  Google Scholar 

  33. 33.

    Fu YH, et al. Variation of the CGG repeat at the fragile X site results in genetic instability: resolution of the Sherman paradox. Cell. 1991;67:1047–58.

    CAS  Article  Google Scholar 

  34. 34.

    Richards RI, et al. Evidence of founder chromosomes in fragile X syndrome. Nat Genet. 1992;1:257–60.

    CAS  Article  Google Scholar 

  35. 35.

    Haataja R, Vaisanen ML, Li M, Ryynanen M, Leisti J. The fragile X syndrome in Finland: demonstration of a founder effect by analysis of microsatellite haplotypes. Hum Genet. 1994;94:479–83.

    CAS  Article  Google Scholar 

  36. 36.

    Chiurazzi P, Macpherson J, Sherman S, Neri G. Significance of linkage disequilibrium between the fragile X locus and its flanking markers. Am J Med Genet. 1996;64:203–8.

    CAS  Article  Google Scholar 

  37. 37.

    Gunter C, et al. Re-examination of factors associated with expansion of CGG repeats using a single nucleotide polymorphism in FMR1. Hum Mol Genet. 1998;7:1935–46.

    CAS  Article  Google Scholar 

  38. 38.

    Warby SC, et al. CAG expansion in the Huntington disease gene is associated with a specific and targetable predisposing haplogroup. Am J Hum Genet. 2009;84:351–66.

    CAS  Article  Google Scholar 

  39. 39.

    Mok K, et al. Chromosome 9 ALS and FTD locus is probably derived from a single founder. Neurobiol Aging. 2012;33:209 e3–8.

    Article  Google Scholar 

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Acknowledgments

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).

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Correspondence to Joseph Piven or Patrick F. Sullivan.

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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

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