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.

Figure 1.. FXS case-control GWAS.

(A) Quantile-quantile plot for logistic regression of male FXS cases and GABC controls (including ancestry principle components). The observed P-values conform closely to the null except for five SNPs in the FMR1 region. The shaded region indicates the expected 95% probability interval for ordered P-values. (B) Manhattan plot for the GWAS of male FXS cases and GABC controls (logistic regression including ancestry principle components). The X-axis is chromosomal position from 1ptel to Xqtel. The Y-axis is -log₁₀(P). Genome-wide significant SNPs near FMR1 are indicated. (C) Detail of FMR1 region (hg19, chrX:146850000–147040000). Tracks are: GENCODE gene annotations; positions of FRAXAC1, FRAXAC2, and promoter CGG repeat; selected ChIP-seq marks; SNP positions and -log₁₀(P) for SNPs in the fine-mapping study and in the GWAS; DNA-DNA chromosomal looping from 5C based on the FMR1 promoter; and open chromatin in pre-frontal cortex of 9 adult schizophrenia (SCZ) cases and 9 fetal samples.