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Unrecognized sequence homologies may confound genome-wide association studies.

Galichon P, Mesnard L, Hertig A, Stengel B, Rondeau E - Nucleic Acids Res. (2012)

Bottom Line: Genome-wide association studies (GWAS) have become a preferred method to identify new genetic susceptibility loci.Using genetic differences between male and female subjects as a model to study the effect of one specific genomic region on the whole SNP microarray, we provide strong evidence that the use of standard methods for GWAS can be misleading.We suggest a new systematic quality control step in the biological interpretation of previous and future GWAS.

View Article: PubMed Central - PubMed

Affiliation: INSERM UMR S702, Université Pierre et Marie Curie - Paris 6, 75006 Paris, France. galichon@orange.fr

ABSTRACT
Genome-wide association studies (GWAS) have become a preferred method to identify new genetic susceptibility loci. This technique aims to understanding the molecular etiology of common diseases, but in many cases, it has led to the identification of loci with no obvious biological relevance. Herein, we show that previously unrecognized sequence homologies have caused single-nucleotide polymorphism (SNP) microarrays to incorrectly associate a phenotype to a given locus when in fact the linkage is to another distant locus. Using genetic differences between male and female subjects as a model to study the effect of one specific genomic region on the whole SNP microarray, we provide strong evidence that the use of standard methods for GWAS can be misleading. We suggest a new systematic quality control step in the biological interpretation of previous and future GWAS.

Show MeSH
Schematic view of the hybridization of DNA to a microarray probe. Three possibilities include theoretical hybridization, rogue hybridization with a homolog, and bulk hybridization of genomic DNA that sequesters the restriction fragment away from the probe. (1) Hybridization of the target sequence with the probe, according to theory. (2) Hybridization of a sex chromosome sequence with the probe of a homologous autosomal SNP, competing with the theoretical autosomal restriction fragment. (3) Hybridization of a sex chromosome restriction fragment with an autosomal SNP restriction fragment, competing with the microarrays' oligonucleotide probe. (4) Oligonucleotide probes for sex chromosomes’ SNPs hybridize with the same restriction fragment as probes for autosomal SNPs and are thus statistically correlated.
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gks169-F3: Schematic view of the hybridization of DNA to a microarray probe. Three possibilities include theoretical hybridization, rogue hybridization with a homolog, and bulk hybridization of genomic DNA that sequesters the restriction fragment away from the probe. (1) Hybridization of the target sequence with the probe, according to theory. (2) Hybridization of a sex chromosome sequence with the probe of a homologous autosomal SNP, competing with the theoretical autosomal restriction fragment. (3) Hybridization of a sex chromosome restriction fragment with an autosomal SNP restriction fragment, competing with the microarrays' oligonucleotide probe. (4) Oligonucleotide probes for sex chromosomes’ SNPs hybridize with the same restriction fragment as probes for autosomal SNPs and are thus statistically correlated.

Mentions: Schematics of the two mechanisms that we have identified as possibly biasing SNP association results are presented in Figure 3.Figure 3.


Unrecognized sequence homologies may confound genome-wide association studies.

Galichon P, Mesnard L, Hertig A, Stengel B, Rondeau E - Nucleic Acids Res. (2012)

Schematic view of the hybridization of DNA to a microarray probe. Three possibilities include theoretical hybridization, rogue hybridization with a homolog, and bulk hybridization of genomic DNA that sequesters the restriction fragment away from the probe. (1) Hybridization of the target sequence with the probe, according to theory. (2) Hybridization of a sex chromosome sequence with the probe of a homologous autosomal SNP, competing with the theoretical autosomal restriction fragment. (3) Hybridization of a sex chromosome restriction fragment with an autosomal SNP restriction fragment, competing with the microarrays' oligonucleotide probe. (4) Oligonucleotide probes for sex chromosomes’ SNPs hybridize with the same restriction fragment as probes for autosomal SNPs and are thus statistically correlated.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3367202&req=5

gks169-F3: Schematic view of the hybridization of DNA to a microarray probe. Three possibilities include theoretical hybridization, rogue hybridization with a homolog, and bulk hybridization of genomic DNA that sequesters the restriction fragment away from the probe. (1) Hybridization of the target sequence with the probe, according to theory. (2) Hybridization of a sex chromosome sequence with the probe of a homologous autosomal SNP, competing with the theoretical autosomal restriction fragment. (3) Hybridization of a sex chromosome restriction fragment with an autosomal SNP restriction fragment, competing with the microarrays' oligonucleotide probe. (4) Oligonucleotide probes for sex chromosomes’ SNPs hybridize with the same restriction fragment as probes for autosomal SNPs and are thus statistically correlated.
Mentions: Schematics of the two mechanisms that we have identified as possibly biasing SNP association results are presented in Figure 3.Figure 3.

Bottom Line: Genome-wide association studies (GWAS) have become a preferred method to identify new genetic susceptibility loci.Using genetic differences between male and female subjects as a model to study the effect of one specific genomic region on the whole SNP microarray, we provide strong evidence that the use of standard methods for GWAS can be misleading.We suggest a new systematic quality control step in the biological interpretation of previous and future GWAS.

View Article: PubMed Central - PubMed

Affiliation: INSERM UMR S702, Université Pierre et Marie Curie - Paris 6, 75006 Paris, France. galichon@orange.fr

ABSTRACT
Genome-wide association studies (GWAS) have become a preferred method to identify new genetic susceptibility loci. This technique aims to understanding the molecular etiology of common diseases, but in many cases, it has led to the identification of loci with no obvious biological relevance. Herein, we show that previously unrecognized sequence homologies have caused single-nucleotide polymorphism (SNP) microarrays to incorrectly associate a phenotype to a given locus when in fact the linkage is to another distant locus. Using genetic differences between male and female subjects as a model to study the effect of one specific genomic region on the whole SNP microarray, we provide strong evidence that the use of standard methods for GWAS can be misleading. We suggest a new systematic quality control step in the biological interpretation of previous and future GWAS.

Show MeSH