Association analysis of two candidate phospholipase genes that map to the chromosome 15q15.1‐15.3 region associated with reading disability

Abstract

Molecular genetic studies have suggested a reading disability (RD, dyslexia) susceptibility locus on chromosome 15q. We have previously mapped this locus by association to the region surrounding D15S994. Very little is known about the neurobiological processes involved in RD, and therefore selecting positional candidate genes for analysis based upon function is difficult. Nevertheless we were able to identify two functional candidates based upon existing hypotheses. Both were phospholipase genes, phospholipase C beta 2 (PLCB2) and phospholipase A2, group IVB (cytosolic; PLA2G4B). D15S944 is located within PLCB2 and is 1.6 Mb from PLA2G4B. We examined each gene for association using a mixed direct and indirect association approach, a case (n = 164)/control (n = 174) sample, and a partially overlapping sample of 178 RD parent-proband trios from South Wales and England. Mutation analysis revealed 14 sequence variants in PLCB2 and 33 variants in PLA2G4B. All non-synonymous SNPs were genotyped as were SNPs across each gene with maximum distance between SNPs of 6 kb. Case-control analyses revealed modest evidence (0.01 < P < 0.05) for association between a single variant in PLCB2 and two variants in PLA2G4B. However, association was not confirmed in the family based sample. As the latter sample has previously generated replicated significant evidence for association between RD and markers/haplotypes surrounding D15S944, it should have sufficient power to detect association to variants in susceptibility gene itself. We conclude that neither gene accounts for the association signal we previously observed. As these are the only clear cut functional candidate genes in the region, identification of the putative susceptibility locus for RD on 15q will require more methodical non-hypothesis driven positional cloning approaches.

The genetics of developmental dyslexia

“…The translocation disrupted a gene EKN1, now known as dyslexia susceptibility 1 candidate 1 (DYX1C1), which mapped some 15 Mb from the signal reported by Morris et al 37 In the same study, Taipale et al 39 reported evidence for association between DD and a À3G4A SNP located three bases 5 0 to the ATG translational start site that disrupts three predicted transcription factor binding sites and also a 1249 G4T SNP that introduces a stop codon and is predicted to encode a protein truncated by four amino acids. Four studies have subsequently failed to replicate the specific associations with these putative functional variants.…”

Dyslexia and DYX1C1: deficits in reading and spelling associated with a missense mutation

“…However, the results to date suggest that although DYX1C1 is implicated as a candidate, rs3743205 and rs61761345 are at best a rare cause of reading disability, 21,23,32 perhaps specific to the Finnish family or a genetic background. Studies therefore turned to genes in nearby regions, 35 although no candidates have been identified to date, 36 and to the analyses of a small number of additional SNPs in DYX1C1, again without success to date. 37 Thus, although DYX1C1 may be a susceptibility gene for developmental dyslexia, the causal alleles are unknown.…”

Genes, cognition and dyslexia: learning to read the genome

“…(During searches for genetic risk factors, a chromosomal interval that has been highlighted by linkage/association studies can be assigned an official locus symbol by the international Gene Nomenclature Committee, even before a specific gene has been implicated.) It has proved difficult to determine a precise location; whereas some studies highlight 15q15.1 [26,27,29], others point to markers in 15q21, mapping at least 8 million nucleotides away [24,25,28].…”