Background Leucine-rich repeat kinase 2 (LRRK2) is known to harbor highly penetrant mutations linked to familial parkinsonism. However, its full polymorphic variability in relationship to Parkinson’s disease (PD) risk has not been systematically assessed. Methods We examined the frequency pathogenicity of 121 exonic LRRK2 variants in three ethnic series (Caucasian [N=12,590], Asian [N=2,338] and Arab-Berber [N=612]) consisting of 8,611 patients and 6,929 control subjects from 23 separate sites of the Genetic Epidemiology of Parkinson’s Disease Consortium. Findings Excluding carriers of previously known pathogenic mutations, new independent risk associations were found for polymorphic variants in Caucasian (p.M1646T, OR: 1.43, 95% CI: 1.15 – 1.78, P=0.0012) and Asian (p.A419V, OR: 2.27, 95% CI: 1.35 – 3.83, P=0.0011) populations. In addition, a protective haplotype was observed at >5% frequency (p.N551K-p.R1398H-p.K1423K) in the Caucasian and Asian series’, with a similar finding in the small Arab-Berber series that requires further study (combined 3-series OR: 0.82, 95% CI: 0.72 – 0.94, P=0.0043). Of the two previously reported Asian risk variants p.G2385R was found to be associated with disease (OR: 1.73, 95% CI: 1.20 – 2.49, P=0.0026) but no association was observed for p.R1628P (OR: 0.62, 95% CI: 0.36 – 1.07, P=0.087). Also in the Arab-Berber series, p.Y2189C showed potential evidence of risk association with PD (OR: 4.48, 95% CI: 1.33 – 15.09, P=0.012). Of note, two variants (p.I1371V and p.T2356I) which have been previously proposed as pathogenic were observed in patient and control subjects at the same frequency. Interpretation LRRK2 offers an example where multiple rare and common genetic variants in the same gene have independent effects on disease risk. Lrrk2, and the pathway in which it functions, is important in the etiology and pathogenesis of a greater proportion of patients with PD than previously believed. Funding The present study and original funding for the GEO-PD Consortium was supported by grants from Michael J. Fox Foundation. Studies at individual sites were supported by a number of funding agencies world-wide.

No abstract

Variants within the leucine-rich repeat kinase 2 gene are recognized as the most frequent genetic cause of Parkinson’s disease. Leucine-rich repeat kinase 2 variation related to susceptibility to disease displays many features that reflect the nature of complex late-onset sporadic disorders, such as Parkinson’s disease. The Genetic Epidemiology of Parkinson’s disease consortium recently performed the largest genetic association study for variants in the leucine-rich repeat kinase 2 gene across 23 different sites in 15 countries. Herein we detail the allele frequencies for the novel risk factors (p.A419V and p.M1646T) and the protective haplotype (p.N551K-R1398H-K1423K) reported in the original publication. Simple population allele frequencies can not only provide an insight into the clinical relevance of specific variants but also help genetically define patient groups. Establishing individual patient-based genomic susceptibility profiles incorporating both risk and protective factors will determine future diagnostic and treatment strategies.

Three patients suffering from acquired pulmonary stenosis are described resulting from compression of the main pulmonary artery by anterior mediastinal teratoma, Hodgkin's disease, and aneurysm of the ascending aorta, respectively; also four others who had compression of the right or left primary branch of the pulmonary artery. The pulmonary artery compression was demonstrated angiographically in every case, and in the patient with right and left pulmonary artery compression the main pulmonary artery pressure tracing was characteristic of bilateral pulmonary artery stenosis. Cardiac catheterization and selective angiography are indicated in patients who have evidence of right ventricular outflow obstruction to determine the site and severity of the obstruction and to differentiate between extrinsic compression and intrinsic stenosis.There are two main types of acquired pulmonary stenosis; both are rare. The first is due to intrinsic disease of the pulmonary valve itself. The second results from extrinsic compression of the pulmonary artery and it is this with which we are concerned here. We believe it to be more common than has been realized, mainly because angiographic studies are not usually carried out on these patients.In this paper we report three cases of acquired compression of the main pulmonary artery and four of compression of its right or left primary branch. All patients have been studied by right heart catheterization and angiography at Brompton Hospital during the past four years. CASE REPORTS CASE 1 (E. T.) A completely symptom-free girl of 15 years was found on routine chest radiography to have a mass at the left hilum.On examination there was a loud pulmonary systolic ejection murmur and thrill and a single second sound. Abnormal pulsation was palpable in the second and third left intercostal spaces near the sternal edge. The electrocardiogram showed a mean frontal QRS vector of + 110' and suggested mild right ventricular hypertrophy. Chest radiography showed an oval mass in the left hilar region which measured 10 cm. in its long diameter and was continuous with the mediastinal shadow (Fig. 1). In the lateral view this mass lay anteriorly and contained a fleck of calcification. The heart appeared normal.Cardiac catheterization showed a right ventricular pressure of 90/0 mm. Hg. and a right pulmonary artery pressure of 17/3 mm. Hg. The left pulmonary artery could not be entered. The cardiac output was 4 0 1./min. and pulmonary vascular resistance 1-7units.An angiocardiogram showed that the mass was compressing and displacing the pulmonary infundibulum and main pulmonary artery downwards and backwards. The mass itself did not opacify (Figs 2 and 3).Left thoracotomy revealed a smooth, pale yellow, cystic mass, approximately 10x 7*5 cm., protruding from the mediastinum towards the left. Medially and inferiorly the mass contained a soft cystic area which rested on the pericardium over the region of the pulmonary valve, and a firmer more solid bar of tumour extended backwards from this above and lat...

ObjectivesTo test for social structural effects on the gender paradox in suicidal behaviour.MethodsWe analyzed newspaper reports of completed and attempted suicides in the Scottish city of Dundee during the mass movement of women into the paid labour force in the 19th and early 20th Centuries. We calculated rates of suicides per 100,000 of the male and female populations.ResultsWe found that the female suicide rate dropped during this time period, whereas there was only a significant reduction in attempted suicide amongst men.ConclusionsOur understanding, and action to prevent, suicide in men and women must take place in the context of our gendered social world.