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Article: Genome-wide association of an integrated osteoporosis-related phenotype: Is there evidence for pleiotropic genes?

TitleGenome-wide association of an integrated osteoporosis-related phenotype: Is there evidence for pleiotropic genes?
Authors
Issue Date2012
PublisherAmerican Society for Bone and Mineral Research. The Journal's web site is located at http://www.jbmr.org/view/0/index.html
Citation
Journal Of Bone And Mineral Research, 2012, v. 27 n. 2, p. 319-330 How to Cite?
AbstractMultiple musculoskeletal traits assessed by various methods at different skeletal sites serve as surrogates for osteoporosis risk. However, it is a challenge to select the most relevant phenotypes for genetic study of fractures. Principal component analyses (PCA) were conducted in participants of the Framingham Osteoporosis Study on 17 measures including bond mineral density (BMD) (hip and spine), heel ultrasound, leg lean mass (LLM), and hip geometric indices, adjusting for covariates (age, height, body mass index [BMI]), in a combined sample of 1180 men and 1758 women, as well as in each sex. Four principal components (PCs) jointly explained ∼69% of the total variability of musculoskeletal traits. PC1, explaining ∼33% of the total variance, was referred to as the component of "Bone strength," because it included the hip and spine BMD as well as several hip cross-sectional properties. PC2 (20.5% variance) was labeled as "Femoral cross-sectional geometry;" PC3 (∼8% variance) captured only ultrasound measures; PC4, explaining ∼7% variance, was correlated with LLM and hip geometry. We then evaluated ∼2.5 mil SNPs for association with PCs 1, 2, and 4. There were genome-wide significant associations (p < 5 × 10 -8) between PC2 and HTR1E (that codes for one of the serotonin receptors) and PC4 with COL4A2 in women. In the sexes-combined sample, AKAP6 was associated with PC2 (p = 1.40 × 10 -7). A single nucleotide polymorphism (SNP) in HTR1E was also associated with the risk of nonvertebral fractures in women (p = 0.005). Functions of top associated genes were enriched for the skeletal and muscular system development (p < 0.05). In conclusion, multivariate combination provides genetic associations not identified in the analysis of primary phenotypes. Genome-wide screening for the linear combinations of multiple osteoporosis-related phenotypes suggests that there are variants with potentially pleiotropic effects in established and novel pathways to be followed up to provide further evidence of their functions. © 2012 American Society for Bone and Mineral Research.
Persistent Identifierhttp://hdl.handle.net/10722/183388
ISSN
2015 Impact Factor: 5.622
2015 SCImago Journal Rankings: 2.773
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorKarasik, Den_US
dc.contributor.authorCheung, CLen_US
dc.contributor.authorZhou, Yen_US
dc.contributor.authorCupples, LAen_US
dc.contributor.authorKiel, DPen_US
dc.contributor.authorDemissie, Sen_US
dc.date.accessioned2013-05-27T07:12:17Z-
dc.date.available2013-05-27T07:12:17Z-
dc.date.issued2012en_US
dc.identifier.citationJournal Of Bone And Mineral Research, 2012, v. 27 n. 2, p. 319-330en_US
dc.identifier.issn0884-0431en_US
dc.identifier.urihttp://hdl.handle.net/10722/183388-
dc.description.abstractMultiple musculoskeletal traits assessed by various methods at different skeletal sites serve as surrogates for osteoporosis risk. However, it is a challenge to select the most relevant phenotypes for genetic study of fractures. Principal component analyses (PCA) were conducted in participants of the Framingham Osteoporosis Study on 17 measures including bond mineral density (BMD) (hip and spine), heel ultrasound, leg lean mass (LLM), and hip geometric indices, adjusting for covariates (age, height, body mass index [BMI]), in a combined sample of 1180 men and 1758 women, as well as in each sex. Four principal components (PCs) jointly explained ∼69% of the total variability of musculoskeletal traits. PC1, explaining ∼33% of the total variance, was referred to as the component of "Bone strength," because it included the hip and spine BMD as well as several hip cross-sectional properties. PC2 (20.5% variance) was labeled as "Femoral cross-sectional geometry;" PC3 (∼8% variance) captured only ultrasound measures; PC4, explaining ∼7% variance, was correlated with LLM and hip geometry. We then evaluated ∼2.5 mil SNPs for association with PCs 1, 2, and 4. There were genome-wide significant associations (p < 5 × 10 -8) between PC2 and HTR1E (that codes for one of the serotonin receptors) and PC4 with COL4A2 in women. In the sexes-combined sample, AKAP6 was associated with PC2 (p = 1.40 × 10 -7). A single nucleotide polymorphism (SNP) in HTR1E was also associated with the risk of nonvertebral fractures in women (p = 0.005). Functions of top associated genes were enriched for the skeletal and muscular system development (p < 0.05). In conclusion, multivariate combination provides genetic associations not identified in the analysis of primary phenotypes. Genome-wide screening for the linear combinations of multiple osteoporosis-related phenotypes suggests that there are variants with potentially pleiotropic effects in established and novel pathways to be followed up to provide further evidence of their functions. © 2012 American Society for Bone and Mineral Research.en_US
dc.languageengen_US
dc.publisherAmerican Society for Bone and Mineral Research. The Journal's web site is located at http://www.jbmr.org/view/0/index.htmlen_US
dc.relation.ispartofJournal of Bone and Mineral Researchen_US
dc.subject.meshAgeden_US
dc.subject.meshCohort Studiesen_US
dc.subject.meshComputational Biologyen_US
dc.subject.meshFemaleen_US
dc.subject.meshGene Regulatory Networks - Geneticsen_US
dc.subject.meshGenetic Pleiotropy - Geneticsen_US
dc.subject.meshGenome-Wide Association Studyen_US
dc.subject.meshHumansen_US
dc.subject.meshMaleen_US
dc.subject.meshMiddle Ageden_US
dc.subject.meshOsteoporosis - Geneticsen_US
dc.subject.meshOsteoporotic Fractures - Geneticsen_US
dc.subject.meshPhenotypeen_US
dc.subject.meshPolymorphism, Single Nucleotide - Geneticsen_US
dc.subject.meshPrincipal Component Analysisen_US
dc.titleGenome-wide association of an integrated osteoporosis-related phenotype: Is there evidence for pleiotropic genes?en_US
dc.typeArticleen_US
dc.identifier.emailCheung, CL: lung1212@hku.hken_US
dc.identifier.authorityCheung, CL=rp01749en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1002/jbmr.563en_US
dc.identifier.pmid22072498-
dc.identifier.scopuseid_2-s2.0-84862972320en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-84862972320&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume27en_US
dc.identifier.issue2en_US
dc.identifier.spage319en_US
dc.identifier.epage330en_US
dc.identifier.isiWOS:000299373600011-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridKarasik, D=7004384589en_US
dc.identifier.scopusauthoridCheung, CL=14520953400en_US
dc.identifier.scopusauthoridZhou, Y=23053503600en_US
dc.identifier.scopusauthoridCupples, LA=7007090535en_US
dc.identifier.scopusauthoridKiel, DP=7005526959en_US
dc.identifier.scopusauthoridDemissie, S=35292066400en_US

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