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Genome-wide analysis of epistasis in body mass index using multiple human populations.

Wei WH, Hemani G, Gyenesei A, Vitart V, Navarro P, Hayward C, Cabrera CP, Huffman JE, Knott SA, Hicks AA, Rudan I, Pramstaller PP, Wild SH, Wilson JF, Campbell H, Hastie ND, Wright AF, Haley CS - Eur. J. Hum. Genet. (2012)

Bottom Line: Next we compared sub genome-wide significant SNP interactions (P<5.0E-08) across cohorts to identify common epistatic signals, where SNPs were annotated to genes to test for gene ontology (GO) enrichment.Interactions between the 19 shared epistatic genes and those involving BMI candidate loci (P<5.0E-08) were tested across cohorts and found eight replicated at the SNP level (P<0.05) in at least one cohort, which were further tested and showed limited replication in a separate European population (n>5000).We conclude that genome-wide analysis of epistasis in multiple populations is an effective approach to provide new insights into the genetic regulation of BMI but requires additional efforts to confirm the findings.

View Article: PubMed Central - PubMed

Affiliation: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK. Wenhua.Wei@igmm.ed.ac.uk

ABSTRACT
We surveyed gene-gene interactions (epistasis) in human body mass index (BMI) in four European populations (n<1200) via exhaustive pair-wise genome scans where interactions were computed as F ratios by testing a linear regression model fitting two single-nucleotide polymorphisms (SNPs) with interactions against the one without. Before the association tests, BMI was corrected for sex and age, normalised and adjusted for relatedness. Neither single SNPs nor SNP interactions were genome-wide significant in either cohort based on the consensus threshold (P=5.0E-08) and a Bonferroni corrected threshold (P=1.1E-12), respectively. Next we compared sub genome-wide significant SNP interactions (P<5.0E-08) across cohorts to identify common epistatic signals, where SNPs were annotated to genes to test for gene ontology (GO) enrichment. Among the epistatic genes contributing to the commonly enriched GO terms, 19 were shared across study cohorts of which 15 are previously published genome-wide association loci, including CDH13 (cadherin 13) associated with height and SORCS2 (sortilin-related VPS10 domain containing receptor 2) associated with circulating insulin-like growth factor 1 and binding protein 3. Interactions between the 19 shared epistatic genes and those involving BMI candidate loci (P<5.0E-08) were tested across cohorts and found eight replicated at the SNP level (P<0.05) in at least one cohort, which were further tested and showed limited replication in a separate European population (n>5000). We conclude that genome-wide analysis of epistasis in multiple populations is an effective approach to provide new insights into the genetic regulation of BMI but requires additional efforts to confirm the findings.

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Pair-wise epistatic signals in each study cohort. (a) Pairwise epistatic signals in CROATIA-Vis. (b) Pairwise epistatic signals in CROATIA-Korcula. (c) Pairwise epistatic signals in ORCADES. (d) Pairwise epistatic signals in MICROS.
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fig1: Pair-wise epistatic signals in each study cohort. (a) Pairwise epistatic signals in CROATIA-Vis. (b) Pairwise epistatic signals in CROATIA-Korcula. (c) Pairwise epistatic signals in ORCADES. (d) Pairwise epistatic signals in MICROS.

Mentions: Full pair-wise genome scans found no SNP pairs that passed the genome-wide threshold (−log10 Pint=11.95) in any of the four study cohorts (Figure 1). Considering interaction signals with −log10 Pint >7.3, MICROS had the least number of SNP pairs and consequently the least number of annotated genes, whereas the remaining three cohorts had relatively similar numbers of SNP pairs and annotated genes (Table 2). Five out of the 32 BMI loci (but not the BMI SNPs) were involved in 7 epistatic pairs in CROATIA-Vis: FTO, KCTD15, LRP1B, NEGR1 and PRKD1. Similarly, three BMI loci (NEGR1, NRXN3 and PRKD1) were involved in CROATIA-Korcula, two (FTO and MTCH2) in ORCADES and two (FTO and LRP1B) in MICROS.


Genome-wide analysis of epistasis in body mass index using multiple human populations.

Wei WH, Hemani G, Gyenesei A, Vitart V, Navarro P, Hayward C, Cabrera CP, Huffman JE, Knott SA, Hicks AA, Rudan I, Pramstaller PP, Wild SH, Wilson JF, Campbell H, Hastie ND, Wright AF, Haley CS - Eur. J. Hum. Genet. (2012)

Pair-wise epistatic signals in each study cohort. (a) Pairwise epistatic signals in CROATIA-Vis. (b) Pairwise epistatic signals in CROATIA-Korcula. (c) Pairwise epistatic signals in ORCADES. (d) Pairwise epistatic signals in MICROS.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3400731&req=5

fig1: Pair-wise epistatic signals in each study cohort. (a) Pairwise epistatic signals in CROATIA-Vis. (b) Pairwise epistatic signals in CROATIA-Korcula. (c) Pairwise epistatic signals in ORCADES. (d) Pairwise epistatic signals in MICROS.
Mentions: Full pair-wise genome scans found no SNP pairs that passed the genome-wide threshold (−log10 Pint=11.95) in any of the four study cohorts (Figure 1). Considering interaction signals with −log10 Pint >7.3, MICROS had the least number of SNP pairs and consequently the least number of annotated genes, whereas the remaining three cohorts had relatively similar numbers of SNP pairs and annotated genes (Table 2). Five out of the 32 BMI loci (but not the BMI SNPs) were involved in 7 epistatic pairs in CROATIA-Vis: FTO, KCTD15, LRP1B, NEGR1 and PRKD1. Similarly, three BMI loci (NEGR1, NRXN3 and PRKD1) were involved in CROATIA-Korcula, two (FTO and MTCH2) in ORCADES and two (FTO and LRP1B) in MICROS.

Bottom Line: Next we compared sub genome-wide significant SNP interactions (P<5.0E-08) across cohorts to identify common epistatic signals, where SNPs were annotated to genes to test for gene ontology (GO) enrichment.Interactions between the 19 shared epistatic genes and those involving BMI candidate loci (P<5.0E-08) were tested across cohorts and found eight replicated at the SNP level (P<0.05) in at least one cohort, which were further tested and showed limited replication in a separate European population (n>5000).We conclude that genome-wide analysis of epistasis in multiple populations is an effective approach to provide new insights into the genetic regulation of BMI but requires additional efforts to confirm the findings.

View Article: PubMed Central - PubMed

Affiliation: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK. Wenhua.Wei@igmm.ed.ac.uk

ABSTRACT
We surveyed gene-gene interactions (epistasis) in human body mass index (BMI) in four European populations (n<1200) via exhaustive pair-wise genome scans where interactions were computed as F ratios by testing a linear regression model fitting two single-nucleotide polymorphisms (SNPs) with interactions against the one without. Before the association tests, BMI was corrected for sex and age, normalised and adjusted for relatedness. Neither single SNPs nor SNP interactions were genome-wide significant in either cohort based on the consensus threshold (P=5.0E-08) and a Bonferroni corrected threshold (P=1.1E-12), respectively. Next we compared sub genome-wide significant SNP interactions (P<5.0E-08) across cohorts to identify common epistatic signals, where SNPs were annotated to genes to test for gene ontology (GO) enrichment. Among the epistatic genes contributing to the commonly enriched GO terms, 19 were shared across study cohorts of which 15 are previously published genome-wide association loci, including CDH13 (cadherin 13) associated with height and SORCS2 (sortilin-related VPS10 domain containing receptor 2) associated with circulating insulin-like growth factor 1 and binding protein 3. Interactions between the 19 shared epistatic genes and those involving BMI candidate loci (P<5.0E-08) were tested across cohorts and found eight replicated at the SNP level (P<0.05) in at least one cohort, which were further tested and showed limited replication in a separate European population (n>5000). We conclude that genome-wide analysis of epistasis in multiple populations is an effective approach to provide new insights into the genetic regulation of BMI but requires additional efforts to confirm the findings.

Show MeSH
Related in: MedlinePlus