ena-STUDY-KIS-19-06-2013-15:37:33:850-37
Analysis of targeted exons by selector technology enrichment and SOLID sequencing of DNA from 100 individuals from Finland with dyslexia.
Genetic analyses of common traits have lately been focused on genome-wide association analysis using known markers at varying genomic resolution. Detection of rare and novel variants, however, requires an alternative approach. Using pooled DNA samples, we aimed at evaluating the effectiveness of a targeted sequencing approach to find new single nucleotide variants (SNVs). We selected eleven dyslexia candidate genes (CYP19A1, DCDC2, DIP2A, DYX1C1, GCFC2, KIAA0319, MRPL19, PCNT, PRMT2, ROBO1 and S100B) based on previous literature including association analysis and positional cloning, and sequenced exons as well as surrounding intronic regions in 100 unrelated dyslexic individuals from the Finnish population. Subsequent Sequenom genotyping of each individual from the pools validated 92 SNVs. Multiple SNVs in the CYP19A1 gene encoding aromatase showed significant association with dyslexia in the Finnish sample set. This confirms recently published results and further strengthens the role of aromatase in the biology of reading and spelling. Genotyping of the same set of 92 SNVs in families with dyslexia from the German population revealed that a non-synonymous polymorphism in the DCDC2 gene was significantly associated with severe spelling deficits, suggesting that individuals with severe sub-phenotypes of dyslexia may present with non-synonymous DNA variations. We argue that targeted sequencing of exons in selected genes can be an attractive methodology to identify novel and known single nucleotide variations associated to complex traits.
Genetic analyses of common traits have lately been focused on genome-wide association analysis using known markers at varying genomic resolution. Detection of rare and novel variants, however, requires an alternative approach. Using pooled DNA samples, we aimed at evaluating the effectiveness of a targeted sequencing approach to find new single nucleotide variants (SNVs). We selected eleven dyslexia candidate genes (CYP19A1, DCDC2, DIP2A, DYX1C1, GCFC2, KIAA0319, MRPL19, PCNT, PRMT2, ROBO1 and S100B) based on previous literature including association analysis and positional cloning, and sequenced exons as well as surrounding intronic regions in 100 unrelated dyslexic individuals from the Finnish population. Subsequent Sequenom genotyping of each individual from the pools validated 92 SNVs. Multiple SNVs in the CYP19A1 gene encoding aromatase showed significant association with dyslexia in the Finnish sample set. This confirms recently published results and further strengthens the role of aromatase in the biology of reading and spelling. Genotyping of the same set of 92 SNVs in families with dyslexia from the German population revealed that a non-synonymous polymorphism in the DCDC2 gene was significantly associated with severe spelling deficits, suggesting that individuals with severe sub-phenotypes of dyslexia may present with non-synonymous DNA variations. We argue that targeted sequencing of exons in selected genes can be an attractive methodology to identify novel and known single nucleotide variations associated to complex traits.