Mapping of a blood pressure QTL on chromosome 17 in American Indians of the strong heart family study.
BACKGROUND
Blood pressure (BP) is a complex trait, with a heritability of 30 to 40%. Several genome wide associated BP loci explain only a small fraction of the phenotypic variation. Family studies can provide an important tool for gene discovery by utilizing trait and genetic transmission information among relative-pairs. We have previously described a quantitative trait locus at chromosome 17q25.3 influencing systolic BP in American Indians of the Strong Heart Family Study (SHFS). This locus has been reported to associate with variation in BP traits in family studies of Europeans, African Americans and Hispanics.


METHODS
To follow-up persuasive linkage findings at this locus, we performed comprehensive genotyping in the 1-LOD unit support interval region surrounding this QTL using a multi-step strategy. We first genotyped 1,334 single nucleotide polymorphisms (SNPs) in 928 individuals from families that showed evidence of linkage for BP. We then genotyped a second panel of 306 SNPs in all SHFS participants (N = 3,807) for genes that displayed the strongest evidence of association in the region, and, in a third step, included additional genotyping to better cover the genes of interest and to interrogate plausible candidate genes in the region.


RESULTS
Three genes had multiple SNPs marginally associated with systolic BP (TBC1D16, HRNBP3 and AZI1). In BQTN analysis, used to estimate the posterior probability that any variant in each gene had an effect on the phenotype, AZI1 showed the most prominent findings (posterior probability of 0.66). Importantly, upon correction for multiple testing, none of our study findings could be distinguished from chance.


CONCLUSIONS
Our findings demonstrate the difficulty of follow-up studies of linkage studies for complex traits, particularly in the context of low powered studies and rare variants underlying linkage peaks.
Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA. noraf@unc.edu.
Nora
N
Franceschini
Ran
R
Tao
Lan
L
Liu
Sue
S
Rutherford
Karin
K
Haack
Laura
L
Almasy
Harald Hh
HH
Göring
Sandra
S
Laston
Elisa T
ET
Lee
Lyle G
LG
Best
Richard
R
Fabsitz
Shelley A
SA
Cole
Kari E
KE
North
D001794:Blood Pressure / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics; D002886:Chromosomes, Human, Pair 17; D003598:Cytoskeletal Proteins; D005260:Female; D020690:GTPase-Activating Proteins / Q000235:genetics; D005787:Gene Frequency; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D007198:Indians, North American / Q000235:genetics*; D008126:Lod Score; D008297:Male; D008868:Microtubule Proteins / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D014481:United States / Q000453:epidemiology
C578334:CEP131 protein, human; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D020690:GTPase-Activating Proteins; D008868:Microtubule Proteins; C555060:TBC1D16 protein, human