Adult height is a model polygenic trait, but there has been limited success in identifying the genes underlying its normal variation. To identify genetic variants influencing adult human height, we used genome-wide association data from 13,665 individuals and genotyped 39 variants in an additional 16,482 samples. We identified 20 variants associated with adult height (P < 5 x 10(-7), with 10 reaching P < 1 x 10(-10)). Combined, the 20 SNPs explain approximately 3% of height variation, with a approximately 5 cm difference between the 6.2% of people with 17 or fewer 'tall' alleles compared to the 5.5% with 27 or more 'tall' alleles. The loci we identified implicate genes in Hedgehog signaling (IHH, HHIP, PTCH1), extracellular matrix (EFEMP1, ADAMTSL3, ACAN) and cancer (CDK6, HMGA2, DLEU7) pathways, and provide new insights into human growth and developmental processes. Finally, our results provide insights into the genetic architecture of a classic quantitative trait.

Abstract-The hypothesis that the decreased nitric oxide (NO) availability observed in spontaneously hypertensive stroke-prone rats (SHRSP) is due to excess superoxide (O 2 Ϫ ) was examined. O 2 Ϫ generation, measured by lucigenin chemiluminescence, was studied in 12-to 16-week male and female Wistar-Kyoto rats (WKY) Key Words: superoxide Ⅲ endothelium Ⅲ nitric oxide Ⅲ rats, inbred SHR Ⅲ nitric oxide synthase E ndothelial dysfunction and a relative deficiency in nitric oxide (NO) may be associated with hypertension in humans 1,2 and in some models of experimental hypertension. 3,4 In the spontaneously hypertensive stroke-prone rat (SHRSP), a model of genetic hypertension, we have shown an attenuation of functional basal NO despite increased eNOS enzymatic activity. 5 Although endothelial NO synthase (eNOS) enzymatic activity was greater in SHRSP than in Wistar-Kyoto rats (WKY) when examined in vitro the possibility that the actual amount of eNOS was reduced in SHRSP in vivo could not be excluded from these results. Alternatively, eNOS levels could be similar or elevated but NO availability decreased because of more rapid removal after synthesis. Superoxide anion (O 2 Ϫ ) is produced in the vasculature and can scavenge NO forming peroxynitrite. Increased scavenging of NO by O 2 Ϫ could lead to a decrease in NO availability despite increased synthesis. Raised O 2 Ϫ levels have been reported recently in a number of models of endothelial dysfunction including hypertension, induced by either angiotensin infusion 6 or aortic banding. 7 In the majority of cases the source of excess O 2 Ϫ is uncertain, although involvement of NADH/NADPH oxidases 8 and xanthine oxidase 9 have been suggested.The aim of this study was to examine the hypothesis that the decreased NO availability observed in SHRSP is due to excess O 2 Ϫ , to identify the source of this O 2 Ϫ , and to examine other molecular mechanisms involved such as the expression of the gene-encoding enzyme involved in NO generation in the endothelium (eNOS). Methods AnimalsThree-to 4-month-old male and female WKY and SHRSP were obtained from the colonies established in Glasgow by brother and sister mating as previously described. 9 Blood pressure was measured 1 week before study by tail plethysmography according to our published protocol. 10

Much attention has been focused on the role of nitric oxide in hypertension and cardiovascular disease. More recently, the role of superoxide anion and its interaction with nitric oxide has been investigated in this context. This review will concentrate on the role of superoxide in human and experimental hypertension, paying particular attention to the potential sources of superoxide within the vasculature and discussing some of the molecular mechanisms surrounding its production and dismutation. We discuss what is known about the human superoxide dismutase enzymes. We conclude that the balance between nitric oxide and superoxide is more important than the absolute levels of either alone.