Common-variant associations with fragile X syndrome

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

doi:10.1038/s41380-018-0290-3

Common-variant associations with fragile X syndrome

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

^*Corresponding author for this work

Communication Sciences and Disorders

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

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.

Original language	English (US)
Pages (from-to)	338-344
Number of pages	7
Journal	Molecular Psychiatry
Volume	24
Issue number	3
DOIs	https://doi.org/10.1038/s41380-018-0290-3
State	Published - Mar 1 2019

ASJC Scopus subject areas

Molecular Biology
Cellular and Molecular Neuroscience
Psychiatry and Mental health

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title = "Common-variant associations with fragile X syndrome",

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.",

author = "Crowley, {James J.} and Jin Szatkiewicz and K{\"a}hler, {Anna K.} and Paola Giusti-Rodriguez and Ancalade, {Na Eshia} and Booker, {Jessica K.} and Carr, {Jennifer L.} and Crawford, {Greg E.} and Molly Losh and Stockmeier, {Craig A.} and Taylor, {Annette K.} and Joseph Piven and Sullivan, {Patrick F.}",

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doi = "10.1038/s41380-018-0290-3",

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AU - Crowley, James J.

AU - Szatkiewicz, Jin

AU - Kähler, Anna K.

AU - Giusti-Rodriguez, Paola

AU - Ancalade, Na Eshia

AU - Booker, Jessica K.

AU - Carr, Jennifer L.

AU - Crawford, Greg E.

AU - Losh, Molly

AU - Stockmeier, Craig A.

AU - Taylor, Annette K.

AU - Piven, Joseph

AU - Sullivan, Patrick F.

PY - 2019/3/1

Y1 - 2019/3/1

N2 - 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.

AB - 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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Common-variant associations with fragile X syndrome

Abstract

ASJC Scopus subject areas

UN SDGs

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