Results
Of the 523 WNT signaling genes, 173 contained qualifying RDVs (GATK
PASS, AF < 1%, CADD phred ≥ 20, coverage ≥ 90%) in the MA
myelomeningocele population (S2 Text). When comparing RDV mutational
burden in the 173 genes between the two Hispanic populations, ten genes
associated with a risk for myelomeningocele by yielding Fisher’s exact
test P values below 0.05 and odds ratios above 1 (Table 1). This
included PORCN , CDH2 , PRICKLE2 , CPE ,FUZ , PTPRU , PSMD3 , TNRC6B , PPP2R1A ,
and FERMT2 . Of these, PORCN , CPE , and TNRC6Bwere detected caudally in the closing neural tube in humans (Krupp et
al., 2012). PORCN , CDH2 , and FUZ have been
previously associated with NTD phenotypes in mouse models (Gray et al.,
2009; Heydeck, Zeng, & Liu, 2009; W. Liu et al., 2012; Radice et al.,
1997). This analysis gave a Bonferroni correction value of 2.9 x
10-4, which none of the genes’ P values fell
below.
[t][/t] table 1 near here
In the EA myelomeningocele population, 189 genes contained qualifying
variants (S3 Text). After comparing those 189 genes between the two
European populations, seven genes were associated with a risk for
myelomeningocele by giving P values below 0.05 and an odds ratio
above 1 (Table 1). These genes included DDB1 , SDC1 ,CSNK1G2 , SOSTDC1 , PLCB1 , DVL2 , andTLE3 . Of these, DDB1 , PLCB1 , and DVL2 were
detected in the human neural tube during closure and DVL2 is also
associated with NTDs in mouse models (Hamblet et al., 2002; Krupp et
al., 2012). This analysis gave a Bonferroni correction value of 2.6 x
10-4, which none of the genes’ P values fell
below.
Subjects from both ethnicities tended to have a similar number of genes
that contained qualifying variants, but MA subjects tended to have more
nominally significant disrupted genes (Fig 2). Nominally significant
disrupted genes were identified in 46 (18%) EA and 66 (26%) MA
myelomeningocele subjects. Also, the disrupted genes that associated
with EA myelomeningocele subjects are different from disrupted genes
associated with MA myelomeningocele subjects, i.e. the nominally
significant genes from each comparison did not overlap.
Gene Ontology analysis regarding biological processes of the disrupted
genes in both populations reveals that both groups have disrupted genes
enriched for regulation of WNT signaling and negative regulation of
canonical WNT signaling. However, disrupted genes in only the MA
subjects were enriched for functions involving PCP and SCF-KIT signaling
whereas disrupted genes in only the EA subjects were enriched for genes
associated with myoblast differentiation, inositol phosphate metabolism,
disassembly of the destruction complex, and recruitment of AXIN to the
membrane (Table 2).
[t][/t] table 2 near here