title: Identification of homogeneous genetic architecture of multiple genetically correlated traits by block clustering of genome-wide associations.
abstract: Genome-wide association studies (GWAS) using high-density genotyping platforms offer an unbiased strategy to identify new candidate genes for osteoporosis. It is imperative to be able to clearly distinguish signal from noise by focusing on the best phenotype in a genetic study. We performed GWAS of multiple phenotypes associated with fractures [bone mineral density (BMD), bone quantitative ultrasound (QUS), bone geometry, and muscle mass] with approximately 433,000 single-nucleotide polymorphisms (SNPs) and created a database of resulting associations. We performed analysis of GWAS data from 23 phenotypes by a novel modification of a block clustering algorithm followed by gene-set enrichment analysis. A data matrix of standardized regression coefficients was partitioned along both axes--SNPs and phenotypes. Each partition represents a distinct cluster of SNPs that have similar effects over a particular set of phenotypes. Application of this method to our data shows several SNP-phenotype connections. We found a strong cluster of association coefficients of high magnitude for 10 traits (BMD at several skeletal sites, ultrasound measures, cross-sectional bone area, and section modulus of femoral neck and shaft). These clustered traits were highly genetically correlated. Gene-set enrichment analyses indicated the augmentation of genes that cluster with the 10 osteoporosis-related traits in pathways such as aldosterone signaling in epithelial cells, role of osteoblasts, osteoclasts, and chondrocytes in rheumatoid arthritis, and Parkinson signaling. In addition to several known candidate genes, we also identified PRKCH and SCNN1B as potential candidate genes for multiple bone traits. In conclusion, our mining of GWAS results revealed the similarity of association results between bone strength phenotypes that may be attributed to pleiotropic effects of genes. This knowledge may prove helpful in identifying novel genes and pathways that underlie several correlated phenotypes, as well as in deciphering genetic and phenotypic modularity underlying osteoporosis risk.
authors: Department of Biostatistics, Boston University, Boston, MA, USA.
authors: Mayetri
authors: M
authors: Gupta
authors: Ching-Lung
authors: CL
authors: Cheung
authors: Yi-Hsiang
authors: YH
authors: Hsu
authors: Serkalem
authors: S
authors: Demissie
authors: L Adrienne
authors: LA
authors: Cupples
authors: Douglas P
authors: DP
authors: Kiel
authors: David
authors: D
authors: Karasik
references: J Biol Chem. 2010 Aug 20;285(34):26233-44
references: 20547765
references: Genet Epidemiol. 2000 Dec;19(4):410-21
references: 11108649
references: Arterioscler Thromb Vasc Biol. 2007 Apr;27(4):799-805
references: 17234727
references: J Bone Miner Res. 2010 Feb;25(2):200-10
references: 19874086
references: Trends Genet. 2008 Mar;24(3):103-6
references: 18243400
references: Bone. 2005 Jul;37(1):112-21
references: 15869917
references: J Bone Miner Res. 2005 Jan;20(1):67-74
references: 15619671
references: Osteoporos Int. 2006 Dec;17(12):1726-33
references: 16983459
references: Genome Biol. 2003;4(5):317
references: 12734004
references: Ann Hum Genet. 1986 May;50(2):181-94
references: 3435047
references: J Bone Miner Res. 2008 Dec;23(12):1892-904
references: 18684092
references: Nat Genet. 2009 Nov;41(11):1199-206
references: 19801982
references: BMC Med Genet. 2007 Sep 19;8 Suppl 1:S14
references: 17903296
references: J Bone Miner Res. 2002 Sep;17(9):1718-27
references: 12211443
references: Endocrinology. 2009 Nov;150(11):4989-98
references: 19819979
references: Hum Hered. 2004;58(3-4):131-8
references: 15812169
references: Physiol Genomics. 2008 Sep 17;35(1):55-64
references: 18612082
references: Genet Epidemiol. 2002 Jan;22(1):12-25
references: 11754470
references: J Bone Miner Res. 2001 May;16(5):901-10
references: 11341335
references: J Bone Miner Res. 2009 Apr;24(4):710-8
references: 19063671
references: Am J Med Genet. 2001 Jan 8;105(1):42-4
references: 11424994
references: Am J Epidemiol. 2000 Apr 1;151(7):689-92
references: 10752796
references: Ann N Y Acad Sci. 2010 Mar;1192:376-84
references: 20392263
references: J Bone Miner Res. 2000 Apr;15(4):710-20
references: 10780863
references: Am J Phys Anthropol. 1967 May;26(3):313-7
references: 6035855
references: Proc Int Conf Intell Syst Mol Biol. 2000;8:93-103
references: 10977070
references: PLoS One. 2008 Sep 08;3(9):e3160
references: 18776929
references: Hum Mol Genet. 2009 Jun 15;18(12):2305-16
references: 19336475
references: J Bone Miner Res. 2007 Nov;22(11):1781-90
references: 17638578
references: Osteoporos Int. 1999;9(3):193-5
references: 10450405
references: BMC Genomics. 2008;9 Suppl 1:S4
references: 18366617
references: BMJ. 1996 May 18;312(7041):1254-9
references: 8634613
references: J Biol Chem. 2005 May 20;280(20):19883-7
references: 15778503
references: PLoS Comput Biol. 2007 Apr 13;3(4):e69
references: 17432931
references: Osteoporos Int. 2008 Sep;19(9):1277-82
references: 18301854
references: Bioinformatics. 2005 Dec 1;21(23):4205-8
references: 16188928
references: J Bone Miner Res. 2005 Oct;20(10):1867-77
references: 16160745
references: Gene. 2006 Feb 15;367:1-16
references: 16361069
references: Am J Hum Genet. 2007 Dec;81(6):1278-83
references: 17966091
references: Osteoporos Int. 2006;17(4):527-34
references: 16402164
references: J Am Coll Cardiol. 2005 Jul 5;46(1):142-6
references: 15992648
references: Ann Hum Genet. 2008 Sep;72(Pt 5):696-714
references: 18485052
references: Proc Am Thorac Soc. 2007 Jan;4(1):18-25
references: 17202287
references: Am J Phys Anthropol. 1982 Dec;59(4):461-5
references: 7165042
references: Osteoporos Int. 2008 Jul;19(7):1093-7
references: 18301855
references: Arch Intern Med. 1979 Aug;139(8):857-61
references: 464698
references: J Biol Chem. 2009 Feb 20;284(8):4897-904
references: 19117954
references: IEEE/ACM Trans Comput Biol Bioinform. 2004 Jan-Mar;1(1):24-45
references: 17048406
references: Am J Hum Biol. 2008 Nov-Dec;20(6):663-70
references: 18449921
references: Bone. 2003 Sep;33(3):308-16
references: 13678771
references: Bone. 2007 Mar;40(3):743-50
references: 17079199
references: Nat Rev Genet. 2004 Jul;5(7):545-51
references: 15211356
references: Genet Epidemiol. 2009 Jul;33(5):419-31
references: 19235186
references: Am J Epidemiol. 2007 May 1;165(9):1076-87
references: 17351290
references: Am J Physiol Heart Circ Physiol. 2004 Nov;287(5):H2023-6
references: 15475529
references: J Bone Miner Res. 2001 Dec;16(12):2260-6
references: 11760840
references: J Bone Miner Res. 2010 Jul;25(7):1555-63
references: 20200953
references: Bioinformatics. 2005 Jan 15;21(2):263-5
references: 15297300
references: Wiley Interdiscip Rev Syst Biol Med. 2009 Jul-Aug;1(1):73-88
references: 20046860
references: Osteoporos Int. 2006;17(4):593-9
references: 16447009
references: Br J Radiol. 1993 May;66(785):435-40
references: 8319065
references: Osteoporos Int. 1996;6(1):8-13
references: 8845604
references: Am J Hum Genet. 1998 Oct;63(4):1190-201
references: 9758596
references: Arthritis Rheum. 2002 Apr;46(4):946-52
references: 11953971
references: Nat Genet. 2006 Aug;38(8):904-9
references: 16862161
references: Arthritis Rheum. 1998 Jun;41(6):1064-71
references: 9627016
references: Am J Hum Genet. 2009 Mar;84(3):388-98
references: 19249006
references: Am J Hum Genet. 2009 Mar;84(3):418-23
references: 19268274
references: Osteoporos Int. 1995;5(4):262-70
references: 7492865
references: Hum Mol Genet. 2003 Jul 15;12(14):1745-54
references: 12837697
references: Bone. 2001 Nov;29(5):477-86
references: 11704501
references: Eur J Hum Genet. 2006 May;14(5):535-42
references: 16493445
references: Int J Mol Med. 2006 Jun;17(6):1125-31
references: 16685425
references: Proc Natl Acad Sci U S A. 2007 May 22;104(21):8685-90
references: 17502601
references: Am J Hum Genet. 2010 Feb 12;86(2):229-39
references: 20096396
references: Biometrics. 2005 Mar;61(1):10-6
references: 15737073
references: Genome Res. 2003 Apr;13(4):703-16
references: 12671006
references: J Bone Miner Res. 2001 Aug;16(8):1496-504
references: 11499872