Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants

We have genotyped 14,436 nonsynonymous SNPs (nsSNPs) and 897 major histocompatibility complex (MHC) tag SNPs from 1,000 independent cases of ankylosing spondylitis (AS), autoimmune thyroid disease (AITD), multiple sclerosis (MS) and breast cancer (BC). Comparing these data against a common control dataset derived from 1,500 randomly selected healthy British individuals, we report initial association and independent replication in a North American sample of two new loci related to ankylosing spondylitis, ARTS1 and IL23R, and confirmation of the previously reported association of AITD with TSHR and FCRL3. These findings, enabled in part by increased statistical power resulting from the expansion of the control reference group to include individuals from the other disease groups, highlight notable new possibilities for autoimmune regulation and suggest that IL23R may be a common susceptibility factor for the major 'seronegative' diseases.     

Use of interstate highway overpasses and billboards for nesting by the common raven ( Corvus corax )

Common ravens are usually rather shy birds around their nests and avoid nesting too near human activity. We here report the use of overpasses along heavily traveled Interstate Highway 84 in Idaho and Utah for nest placement. Nests are within 6 m of passing vehicles.     

Mutations in the gene encoding peroxisomal alpha-methylacyl-CoA racemase cause adult-onset sensory motor neuropathy

Sensory motor neuropathy is associated with various inherited disorders including Charcot-Marie-Tooth disease, X-linked adrenoleukodystrophy/adrenomyeloneuropathy and Refsum disease. In the latter two, the neuropathy is thought to result from the accumulation of specific fatty acids. We describe here three patients with elevated plasma concentrations of pristanic acid (a branched-chain fatty acid) and C27-bile-acid intermediates. Two of the patients suffered from adult-onset sensory motor neuropathy. One patient also had pigmentary retinopathy, suggesting Refsum disease, whereas the other patient had upper motor neuron signs in the legs, suggesting adrenomyeloneuropathy. The third patient was a child without neuropathy. In all three patients we discovered a deficiency of alpha-methylacyl-CoA racemase (AMACR). This enzyme is responsible for the conversion of pristanoyl-CoA and C27-bile acyl-CoAs to their (S)-stereoisomers, which are the only stereoisomers that can be degraded via peroxisomal beta-oxidation. Sequence analysis of AMACR cDNA from the patients identified two different mutations that are likely to cause disease, based on analysis in Escherichia coli. Our findings have implications for the diagnosis of adult-onset neuropathies of unknown aetiology.     

Habitat use and subspecific status of Merlins, Falco columbarius , wintering in central Utah

Most ornithological literature for Utah reports the status of the Merlin ( Falco columbarius ) as rare or scarce. Only the most recently published checklists (Behle and Perry 1975, Behle et al. 1985) record it as uncommon. Likewise, a 1998 printed checklist (Utah Ornithological Society 1998) list it as uncommon. Also misrepresented in the literature are the status and distribution of the 3 rather distinct subspecies, each of which occupies dissimilar habitats during the breeding season. We made random observations of Merlins in northern Utah beginning in the 1950s and then studied them continuously between 1992 and 1997 in Utah County, Utah. During the 1992-1997 period, we were able to clearly allocate 95 males and 76 females to subspecies, including within our count 58 falcons trapped (some fitted with radio telemetry). The winter habitat in which they occurred was categorized as either urban (mainly dense residential area) or rural (agricultural lands, dairy farms, or scattered homes). There was a statistically significant ( X 2 F. c. columbarius frequenting urban areas 68% of the time, and prairie parkland-breeding F. c. richardsonii frequenting rural habitats 78% of the time.     

Breeding biology of Mountain Plovers ( Charadrius montanus ) in the Uinta Basin

The known Mountain Plover population breeding on the Myton Bench, Duchesne County, Utah, is small, composed roughly of 30 adults and young after each breeding season. Currently, its location is peripheral to the species main range. This shrub-steppe breeding habitat differs from the shortgrass prairie habitat with which this bird is historically associated. Between 1996 and 1998 we made observations at nesting sites located consistently in 2 concentrated areas surrounded by large tracts of similar habitat. Activity may be focused in these specific areas because of breeding-site fidelity; this behavior is common among most shorebirds and has been documented for the Mountain Plover in Colorado. Also, Mountain Plovers are social and tend to choose nest sites near others. Most nests in Utah were located within close proximity of mounds of white-tailed prairie dogs ( Cynomys leucurus ), and all were situated near roadways or oil well pads. Mountain Plovers were often observed with broods on these bare areas at night. We conclude that Mountain Plovers on the Myton Bench are distributed in clumped breeding colonies within large areas of apparently favorable habitat.     

Genome-wide association and linkage identify modifier loci of lung disease severity in cystic fibrosis at 11p13 and 20q13.2

A combined genome-wide association and linkage study was used to identify loci causing variation in cystic fibrosis lung disease severity. We identified a significant association (P = 3.34 × 10(-8)) near EHF and APIP (chr11p13) in p.Phe508del homozygotes (n = 1,978). The association replicated in p.Phe508del homozygotes (P = 0.006) from a separate family based study (n = 557), with P = 1.49 × 10(-9) for the three-study joint meta-analysis. Linkage analysis of 486 sibling pairs from the family based study identified a significant quantitative trait locus on chromosome 20q13.2 (log(10) odds = 5.03). Our findings provide insight into the causes of variation in lung disease severity in cystic fibrosis and suggest new therapeutic targets for this life-limiting disorder.     

Gonadotropin-releasing hormone analogue binds to luteal cells and inhibits progesterone production.

Although gonadotropin-releasing hormone (GnRH) is believed to mediate the hypothalamic control of pituitary gonadotropin secretion, continuous or repeated administration of GnRH or its agonist analogues has been shown to cause paradoxical antifertility effects in several species, including primates. GnRH-induced interruption of reproductive cycles and pregnancy is associated with diminished progesterone production, implying defective function of the corpus luteum. These luteolytic effects have been attributed to the well recognized desensitising actions of elevated luteinising hormone (LH) levels on ovarian LH receptors and steroidogenesis, subsequent to GnRH-induced gonadotropin release from the anterior pituitary. However, treatment with high doses of exogenous LH did not cause suppression of serum progesterone levels during early pregnancy in rats, whereas a highly active GnRH analogue was effective in this regard. These observations suggested that GnRH and its agonist analogues, given in high or sustained doses, can exert a direct action on the ovary that is independent of the pituitary. This hypothesis was further supported by the ability of GnRH and its agonists to inhibit human chorionic gonadotropin (HCG)-induced ovarian and uterine weight gain in hypophysectomised rats and to delay the onset of puberty in intact female rats. Also, GnRH and its agonist analogues have recently been shown to inhibit steroidogenesis induced by follicle-stimulating hormone (FSH) in cultured granulosa cells, confirming the direct action of such peptides on the ovarian follicle. The marked inhibitory effects of GnRH and its agonists on corpus luteum function suggest that these compounds could exert direct actions by binding to specific receptors on luteal cells. The present experiments, which examine the effects of GnRH agonists on luteal steroidogenesis, demonstrate the existence of such actions and their mediation by specific high-affinity receptor sites present in luteal cell membranes.     

Population structure, differential bias and genomic control in a large-scale, case-control association study

The main problems in drawing causal inferences from epidemiological case-control studies are confounding by unmeasured extraneous factors, selection bias and differential misclassification of exposure. In genetics the first of these, in the form of population structure, has dominated recent debate. Population structure explained part of the significant +11.2% inflation of test statistics we observed in an analysis of 6,322 nonsynonymous SNPs in 816 cases of type 1 diabetes and 877 population-based controls from Great Britain. The remainder of the inflation resulted from differential bias in genotype scoring between case and control DNA samples, which originated from two laboratories, causing false-positive associations. To avoid excluding SNPs and losing valuable information, we extended the genomic control method by applying a variable downweighting to each SNP.