title: Genome-wide linkage screen for stature and body mass index in 3.032 families: evidence for sex- and population-specific genetic effects.
abstract: Stature (adult body height) and body mass index (BMI) have a strong genetic component explaining observed variation in human populations; however, identifying those genetic components has been extremely challenging. It seems obvious that sample size is a critical determinant for successful identification of quantitative trait loci (QTL) that underlie the genetic architecture of these polygenic traits. The inherent shared environment and known genetic relationships in family studies provide clear advantages for gene mapping over studies utilizing unrelated individuals. To these ends, we combined the genotype and phenotype data from four previously performed family-based genome-wide screens resulting in a sample of 9.371 individuals from 3.032 African-American and European-American families and performed variance-components linkage analyses for stature and BMI. To our knowledge, this study represents the single largest family-based genome-wide linkage scan published for stature and BMI to date. This large study sample allowed us to pursue population- and sex-specific analyses as well. For stature, we found evidence for linkage in previously reported loci on 11q23, 12q12, 15q25 and 18q23, as well as 15q26 and 19q13, which have not been linked to stature previously. For BMI, we found evidence for two loci: one on 7q35 and another on 11q22, both of which have been previously linked to BMI in multiple populations. Our results show both the benefit of (1) combining data to maximize the sample size and (2) minimizing heterogeneity by analyzing subgroups where within-group variation can be reduced and suggest that the latter may be a more successful approach in genetic mapping.
authors.affiliation: Department of Molecular Medicine, National Public Health Institute, Helsinki, Finland.
authors.forename: Sampo
authors.initials: S
authors.lastname: Sammalisto
authors.forename: Tero
authors.initials: T
authors.lastname: Hiekkalinna
authors.forename: Karen
authors.initials: K
authors.lastname: Schwander
authors.forename: Sharon
authors.initials: S
authors.lastname: Kardia
authors.forename: Alan B
authors.initials: AB
authors.lastname: Weder
authors.forename: Beatriz L
authors.initials: BL
authors.lastname: Rodriguez
authors.forename: Alessandro
authors.initials: A
authors.lastname: Doria
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Kelly
authors.forename: Gail R
authors.initials: GR
authors.lastname: Bruner
authors.forename: John B
authors.initials: JB
authors.lastname: Harley
authors.forename: Susan
authors.initials: S
authors.lastname: Redline
authors.forename: Emma K
authors.initials: EK
authors.lastname: Larkin
authors.forename: Sanjay R
authors.initials: SR
authors.lastname: Patel
authors.forename: Amy J H
authors.initials: AJ
authors.lastname: Ewan
authors.forename: James L
authors.initials: JL
authors.lastname: Weber
authors.forename: Markus
authors.initials: M
authors.lastname: Perola
authors.forename: Leena
authors.initials: L
authors.lastname: Peltonen
mesh_terms: D001827:Body Height / Q000235:genetics*; D015992:Body Mass Index; D005190:Family; D055106:Genome-Wide Association Study; D006801:Humans; D040641:Quantitative Trait Loci
references.citation: Proc Natl Acad Sci U S A. 1998 Dec 8;95(25):14869-74
references.pmid: 9843982
references.citation: Hum Hered. 2003;55(4):191-201
references.pmid: 14566097
references.citation: Science. 2007 May 11;316(5826):889-94
references.pmid: 17434869
references.citation: Ann Hum Genet. 1998 Jul;62(Pt 4):307-22
references.pmid: 9924609
references.citation: J Clin Invest. 1998 Oct 1;102(7):1345-51
references.pmid: 9769326
references.citation: Bioinformatics. 2001 Aug;17(8):742-3
references.pmid: 11524377
references.citation: Genet Epidemiol. 1999;17 Suppl 1:S605-9
references.pmid: 10597500
references.citation: Nat Genet. 2002 Jan;30(1):97-101
references.pmid: 11731797
references.citation: Hypertension. 2002 Jan;39(1):3-9
references.pmid: 11799070
references.citation: Am J Hum Genet. 2001 Jul;69(1):106-16
references.pmid: 11410839
references.citation: J Hered. 1950 Dec;41(12):317-8
references.pmid: 14824537
references.citation: Nat Genet. 2006 Feb;38(2):218-22
references.pmid: 16429159
references.citation: Behav Genet. 1997 Jul;27(4):325-51
references.pmid: 9519560
references.citation: Eur J Hum Genet. 2008 Mar;16(3):387-90
references.pmid: 18183040
references.citation: Genes Immun. 2002 Oct;3 Suppl 1:S5-S12
references.pmid: 12215896
references.citation: Nat Genet. 2002 Jul;31(3):241-7
references.pmid: 12053178
references.citation: Am J Hum Genet. 2000 Dec;67(6):1460-9
references.pmid: 11078476
references.citation: Twin Res. 2003 Oct;6(5):399-408
references.pmid: 14624724
references.citation: PLoS Genet. 2007 Apr 27;3(4):e61
references.pmid: 17465681
references.citation: Diabetes. 2004 May;53(5):1375-84
references.pmid: 15111509
references.citation: Obes Res. 1994 May;2(3):213-9
references.pmid: 16355479
references.citation: Obes Res. 2003 Nov;11(11):1290-4
references.pmid: 14627748
references.citation: Obes Res. 2003 Feb;11(2):266-73
references.pmid: 12582223
references.citation: Nat Genet. 2007 Oct;39(10):1245-50
references.pmid: 17767157
references.citation: Hum Mol Genet. 2004 Sep 1;13(17):1943-9
references.pmid: 15238506
references.citation: Am J Hum Genet. 2001 Nov;69(5):936-50
references.pmid: 11565063
references.citation: N Engl J Med. 2003 Dec 4;349(23):2211-22
references.pmid: 14657428
references.citation: PLoS Genet. 2007 Jun;3(6):e97
references.pmid: 17559308
references.citation: Am J Hum Genet. 2003 Feb;72(2):340-50
references.pmid: 12506338
references.citation: Curr Opin Genet Dev. 2006 Dec;16(6):630-6
references.pmid: 17055247
references.citation: Am J Respir Crit Care Med. 2004 Jun 15;169(12):1314-21
references.pmid: 15070816
references.citation: Hum Mol Genet. 2002 Oct 1;11(20):2417-23
references.pmid: 12351577
references.citation: Am J Hum Genet. 2004 Oct;75(4):687-92
references.pmid: 15311375
references.citation: Nat Genet. 1997 Mar;15(3):269-72
references.pmid: 9054939
references.citation: Arthritis Rheum. 1997 Sep;40(9):1725
references.pmid: 9324032
references.citation: Science. 2004 Aug 6;305(5685):869-72
references.pmid: 15297675
references.citation: Genet Epidemiol. 2003 May;24(4):302-8
references.pmid: 12687648
references.citation: Am J Med Genet C Semin Med Genet. 2003 Aug 15;121C(1):71-80
references.pmid: 12888987
references.citation: Nature. 2007 Jun 7;447(7145):661-78
references.pmid: 17554300
references.citation: Hum Hered. 2007;64(2):91-6
references.pmid: 17476108
references.citation: Am J Hum Genet. 1998 Jul;63(1):259-66
references.pmid: 9634505
references.citation: BMC Genet. 2003 Dec 31;4 Suppl 1:S76
references.pmid: 14975144
references.citation: Science. 2006 Apr 14;312(5771):279-83
references.pmid: 16614226
references.citation: Annu Rev Genet. 1993;27:205-33
references.pmid: 8122902
references.citation: Nat Genet. 2006 Sep;38(9):1055-9
references.pmid: 16936732
references.citation: J Med Genet. 2005 Dec;42(12):932-9
references.pmid: 15827092
references.citation: Twin Res Hum Genet. 2005 Feb;8(1):16-21
references.pmid: 15836805