Background Genome-wide association studies (GWASs) in Parkinson's disease (PD) have increased the scope of biological knowledge about the disease over the past decade. We sought to use the largest aggregate of GWAS data to identify novel risk loci and gain further insight into disease etiology. Methods We performed the largest meta-GWAS of PD to date, involving the analysis of 7.8M SNPs in 37.7K cases, 18.6K UK Biobank proxy-cases (having a first degree relative with PD), and 1.4M controls. We carried out a meta-analysis of this GWAS data to nominate novel loci. We then evaluated heritable risk estimates and predictive models using this data. We also utilized large gene expression and methylation resources to examine possible functional consequences as well as tissue, cell type and biological pathway enrichments for the identified risk factors. Additionally we examined shared genetic risk between PD and other phenotypes of interest via genetic correlations followed by Mendelian randomization. Findings We identified 90 independent genome-wide significant risk signals across 78 genomic regions, including 38 novel independent risk signals in 37 loci. These 90 variants explained 16-36% of the heritable risk of PD depending on prevalence. Integrating methylation and expression data within a Mendelian randomization framework identified putatively associated genes at 70 risk signals underlying GWAS loci for follow-up functional studies. Tissue-specific expression enrichment analyses suggested PD loci were heavily brain-enriched, with specific neuronal cell types being implicated from single cell data. We found significant genetic correlations with brain volumes, smoking status, and educational attainment. Mendelian randomization between cognitive performance and PD risk showed a robust association. Interpretation These data provide the most comprehensive understanding of the genetic architecture of PD to date by revealing many additional PD risk loci, providing a biological context for these risk factors, and demonstrating that a considerable genetic component of this disease remains unidentified. Funding See supplemental materials (Text S2). lead to earlier detection and refined diagnostics, which may help improve clinical trials (4). The generation of copious amounts of public summary statistics created by this effort relating to both the GWAS and subsequent analyses of gene expression and methylation patterns may be of use to investigators planning follow-up functional studies in stem cells or other cellular screens, allowing them to prioritize targets more efficiently using our data as additional evidence. We hope our findings may have some downstream clinical impact in the future such as improved patient stratification for clinical trials and genetically informed drug targets.

Introduction: Large variability among Alzheimer's disease (AD) cases might impact genetic discoveries and complicate dissection of underlying biological pathways. Methods: Genome Research at Fundacio ACE (GR@ACE) is a genome-wide study of dementia and its clinical endophenotypes, defined based on AD's clinical certainty and vascular burden. We assessed the impact of known AD loci across endophenotypes to generate loci categories. We incorporated gene coexpression data and conducted pathway analysis per category. Finally, to evaluate the effect of heterogeneity in genetic studies, GR@ACE series were meta-analyzed with additional genome-wide association study data sets. Results: We classified known AD loci into three categories, which might reflect the disease clinical heterogeneity. Vascular processes were only detected as a causal mechanism in probable AD. The meta-analysis strategy revealed the ANKRD31-rs4704171 and NDUFAF6-rs10098778 and confirmed SCIMP-rs7225151 and CD33-rs3865444. Discussion: The regulation of vasculature is a prominent causal component of probable AD. GR@ACE meta-analysis revealed novel AD genetic signals, strongly driven by the presence of clinical heterogeneity in the AD series.

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ObjectivesTo assess the 3-month impact on physical function of a program for community-dwelling frail older adults, based on the integration of primary care, geriatric medicine, and community resources, implemented in “real life”.DesignInterventional cohort study.SettingPrimary care in Barcelona, Spain.ParticipantsIndividuals aged ≥80 years (n=134), presenting at least one sign of frailty (i.e., slow gait speed, weakness, memory complaints, involuntary weight loss, poor social support). Intervention: After frailty screening by the primary care team, candidates were referred to a geriatric team (geriatrician + physical therapist), who performed a comprehensive geriatric assessment and designed a tailored multidisciplinary intervention in the community, including a) multi-modal physical activity (PA) sessions, b) promotion of adherence to a Mediterranean diet c) health education and d) medication review.MeasurementsParticipants were assessed based on a comprehensive geriatric assessment including physical performance (Short Physical Performance Battery -SPPB- and gait speed), at baseline and at a three month follow-up.ResultsA total of 112 (83.6%) participants (mean age=80.8 years, 67.9% women) were included in this research. Despite being independent in daily life, participants’ physical performance was impaired (SPPB=7.5, SD=2.1, gait speed=0.71, SD=0.20 m/sec). After three months, 90.2% of participants completed ≥7.5 physical activity sessions. The mean improvements were +1.47 (SD 1.64) points (p<0.001) for SPPB, +0.08 (SD 0.13) m/sec (p<0.001) for gait speed, −5.5 (SD 12.10) sec (p<0.001) for chair stand test, and 53% (p<0.001) improved their balance. Results remained substantially unchanged after stratifying the analyses according to the severity of frailty.ConclusionsOur results suggested that a “real-world” multidisciplinary intervention, integrating primary care, geriatric care, and community services may improve physical function, a marker of frailty, within 3 months. Further studies are needed to address the long-term impact and scalability of this implementation program.