Hacen falta más Lourdes

Hacen falta más Lourdes

Un comentario sobre el trabajo de la Sección Enfermedad de Parkinson y movimientos anormales del Instituto de Neurología en el blog de No + pálidas.

Juvenile Huntington’s Disease: The Cruel Mutation

Juvenile Huntington’s Disease: The Cruel Mutation

Using genome-wide complex trait analysis to quantify ‘missing heritability’ in Parkinson's disease

Using genome-wide complex trait analysis to quantify ‘missing heritability’ in Parkinson's disease

Margaux F. Keller1,2, Mohamad Saad3,4, Jose Bras5, Francesco Bettella7, Nayia Nicolaou8, Javier Simón-Sánchez8, Florian Mittag3, Finja Büchel3, Manu Sharma9,10, J. Raphael Gibbs1,5, Claudia Schulte9,10, Valentina Moskvina11,12, Alexandra Durr13,14,15,16, Peter Holmans11,12, Laura L. Kilarski11,12, Rita Guerreiro5, Dena G. Hernandez1,5, Alexis Brice13,14,15,16, Pauli Ylikotila17, Hreinn Stefánsson7, Kari Majamaa18, Huw R. Morris11,12, Nigel Williams11,12, Thomas Gasser9,10, Peter Heutink7, Nicholas W. Wood5,6, John Hardy5, Maria Martinez3,4, Andrew B. Singleton1 and Michael A. Nalls1,* for the International Parkinson's Disease Genomics Consortium (IPDGC) and The Wellcome Trust Case Control Consortium 2 (WTCCC2)†
+ Author Affiliations

1Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA,
2Department of Biological Anthropology, Temple University, Philadelphia, PA, USA,
3Institut National de la Sante et de la Recherche Medicale, UMR 1043, Centre de Physiopathologie de Toulouse-Purpan, Toulouse, France,
4Paul Sabatier University, Toulouse, France
5Department of Molecular Neuroscience, Institute of Neurology and
6UCL Genetics Institute, University College London, London, UK
7deCODE genetics, Scientific Services, Sturlugata 8, IS-101 Reykjavik, Iceland,
8Department of Clinical Genetics, Section of Medical Genomics, VU University Medical Centre, Amsterdam, The Netherlands,
9Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tubingen, Tübingen, Germany,
10Deutsches Zentrum fur Neurodegenerative Erkrangungen (German Center for Neurodegenerative Diseases), Tubingen, Germany
11Institute of Psychological Medicine and Clinical Neurosciences and
12Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, UK
13Université Pierre et Marie Curie-Paris, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière, UMR-S975, Paris, France,
14Département de Génétique, AP-HP, Hôpital de la Salpêtrière, Paris, France,
15Institut National de la Sante et de la Recherche Medicale, UMR-S975 (Formerly UMR-S679), Paris, France,
16Centre National de la Recherche Scientifique, UMR-7225, Paris, France,
17Department of Neurology, Turku University Hospital and University of Turku, Finland and
18Department of Clinical Medicine, Neurology, University of Oulu, Finland
↵*To whom correspondence should be addressed at: Molecular Genetics Section, Laboratory of Neurogenetics, NIA, NIH Building 35, 35 Convent Drive, Bethesda, MD 20892, USA. Tel: +1 3014513831; Fax: +1 3014517295; Email: nallsm@mail.nih.gov
Received April 20, 2012.
Revision received July 23, 2012.
Accepted August 1, 2012.
Abstract

Genome-wide association studies (GWASs) have been successful at identifying single-nucleotide polymorphisms (SNPs) highly associated with common traits; however, a great deal of the heritable variation associated with common traits remains unaccounted for within the genome. Genome-wide complex trait analysis (GCTA) is a statistical method that applies a linear mixed model to estimate phenotypic variance of complex traits explained by genome-wide SNPs, including those not associated with the trait in a GWAS. We applied GCTA to 8 cohorts containing 7096 case and 19 455 control individuals of European ancestry in order to examine the missing heritability present in Parkinson's disease (PD). We meta-analyzed our initial results to produce robust heritability estimates for PD types across cohorts. Our results identify 27% (95% CI 17–38, P = 8.08E − 08) phenotypic variance associated with all types of PD, 15% (95% CI −0.2 to 33, P = 0.09) phenotypic variance associated with early-onset PD and 31% (95% CI 17–44, P = 1.34E − 05) phenotypic variance associated with late-onset PD. This is a substantial increase from the genetic variance identified by top GWAS hits alone (between 3 and 5%) and indicates there are substantially more risk loci to be identified. Our results suggest that although GWASs are a useful tool in identifying the most common variants associated with complex disease, a great deal of common variants of small effect remain to be discovered.

Published by Oxford University Press 2012

Autorretratos

El artista William Utermohlen registra, en una serie de autorretratos, la evolución de su enfermedad de Alzheimer.

Self-Portraits of William Utermohlen: 1955 - 2000.

TREM2 Variants in Alzheimer's Disease — NEJM

TREM2 Variants in Alzheimer's Disease — NEJM

Large-scale replication and heterogeneity in Parkinson disease genetic loci.

Neurology. 2012 Aug 14;79(7):659-67. doi: 10.1212/WNL.0b013e318264e353. Epub 2012 Jul 11.
Large-scale replication and heterogeneity in Parkinson disease genetic loci.

Sharma M, Ioannidis JP, Aasly JO, Annesi G, Brice A, Van Broeckhoven C, Bertram L, Bozi M, Crosiers D, Clarke C, Facheris M, Farrer M, Garraux G, Gispert S, Auburger G, Vilariño-Güell C, Hadjigeorgiou GM, Hicks AA, Hattori N, Jeon B, Lesage S, Lill CM, Lin JJ, Lynch T, Lichtner P, Lang AE, Mok V, Jasinska-Myga B, Mellick GD, Morrison KE, Opala G, Pramstaller PP, Pichler I, Park SS, Quattrone A, Rogaeva E, Ross OA, Stefanis L, Stockton JD, Satake W, Silburn PA, Theuns J, Tan EK, Toda T, Tomiyama H, Uitti RJ, Wirdefeldt K, Wszolek Z, Xiromerisiou G, Yueh KC, Zhao Y, Gasser T, Maraganore D, Krüger R; GEO-PD Consortium.
Collaborators (103)

Source
Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. manu.sharma@uni-tuebingen.de

Abstract
OBJECTIVE:
Eleven genetic loci have reached genome-wide significance in a recent meta-analysis of genome-wide association studies in Parkinson disease (PD) based on populations of Caucasian descent. The extent to which these genetic effects are consistent across different populations is unknown.
METHODS:
Investigators from the Genetic Epidemiology of Parkinson's Disease Consortium were invited to participate in the study. A total of 11 SNPs were genotyped in 8,750 cases and 8,955 controls. Fixed as well as random effects models were used to provide the summary risk estimates for these variants. We evaluated between-study heterogeneity and heterogeneity between populations of different ancestry.
RESULTS:
In the overall analysis, single nucleotide polymorphisms (SNPs) in 9 loci showed significant associations with protective per-allele odds ratios of 0.78-0.87 (LAMP3, BST1, and MAPT) and susceptibility per-allele odds ratios of 1.14-1.43 (STK39, GAK, SNCA, LRRK2, SYT11, and HIP1R). For 5 of the 9 replicated SNPs there was nominally significant between-site heterogeneity in the effect sizes (I(2) estimates ranged from 39% to 48%). Subgroup analysis by ethnicity showed significantly stronger effects for the BST1 (rs11724635) in Asian vs Caucasian populations and similar effects for SNCA, LRRK2, LAMP3, HIP1R, and STK39 in Asian and Caucasian populations, while MAPT rs2942168 and SYT11 rs34372695 were monomorphic in the Asian population, highlighting the role of population-specific heterogeneity in PD.
CONCLUSION:
Our study allows insight to understand the distribution of newly identified genetic factors contributing to PD and shows that large-scale evaluation in diverse populations is important to understand the role of population-specific heterogeneity.

Comment in
Genetic heterogeneity in Parkinson disease: the meaning of GWAS and replication studies. [Neurology. 2012]

Un test para Enfermedad de Parkinson en una llamada de teléfono

TED: Max Little: A test for Parkinson’s with a phone call.

En los países como Uruguay, donde tenemos un sistema de salud remotamente parecido a algo adecuado y accesible, la utilidad es menor y lo que el conferencista dice no es igualmente aplicable. Además, los beneficios de ir a un neurólogo van mucho más allá del diagnóstico y el tratamiento. Aquí un post sobre el tema, no centrado en la Neurología sino en la Medicina en general. 

De todos modos el sistema es muy interesante y una innovación potencialmente útil.

via: Nacho F. Mata: @nachogenePD

Years before diagnosis, quality of life declines for Parkinson's disease patients

Years before diagnosis, quality of life declines for Parkinson's disease patients

Metanálisis de GWAS en EP: nuevo locus, RIT2

Ann Neurol. 2012 Mar;71(3):370-84. doi: 10.1002/ana.22687.

Meta-analysis of Parkinson's disease: identification of a novel locus, RIT2.

Pankratz N, Beecham GW, DeStefano AL, Dawson TM, Doheny KF, Factor SA, Hamza TH, Hung AY, Hyman BT, Ivinson AJ, Krainc D, Latourelle JC, Clark LN, Marder K, Martin ER, Mayeux R, Ross OA, Scherzer CR, Simon DK, Tanner C, Vance JM, Wszolek ZK, Zabetian CP, Myers RH, Payami H, Scott WK, Foroud T; PD GWAS Consortium.
Collaborators (739)

Source
Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Abstract

OBJECTIVE:
Genome-wide association (GWAS) methods have identified genes contributing to Parkinson's disease (PD); we sought to identify additional genes associated with PD susceptibility.

METHODS:
A 2-stage design was used. First, individual level genotypic data from 5 recent PD GWAS (Discovery Sample: 4,238 PD cases and 4,239 controls) were combined. Following imputation, a logistic regression model was employed in each dataset to test for association with PD susceptibility and results from each dataset were meta-analyzed. Second, 768 single-nucleotide polymorphisms (SNPs) were genotyped in an independent Replication Sample (3,738 cases and 2,111 controls).

RESULTS:
Genome-wide significance was reached for SNPs in SNCA (rs356165; G: odds ratio [OR]=1.37; p=9.3×10(-21)), MAPT (rs242559; C: OR=0.78; p=1.5×10(-10)), GAK/DGKQ (rs11248051; T: OR=1.35; p=8.2×10(-9)/rs11248060; T: OR=1.35; p=2.0×10(-9)), and the human leukocyte antigen (HLA) region (rs3129882; A: OR=0.83; p=1.2×10(-8)), which were previously reported. The Replication Sample confirmed the associations with SNCA, MAPT, and the HLA region and also with GBA (E326K; OR=1.71; p=5×10(-8) Combined Sample) (N370; OR=3.08; p=7×10(-5) Replication sample). A novel PD susceptibility locus, RIT2, on chromosome 18 (rs12456492; p=5×10(-5) Discovery Sample; p=1.52×10(-7) Replication sample; p=2×10(-10) Combined Sample) was replicated. Conditional analyses within each of the replicated regions identified distinct SNP associations within GBA and SNCA, suggesting that there may be multiple risk alleles within these genes.

INTERPRETATION:
We identified a novel PD susceptibility locus, RIT2, replicated several previously identified loci, and identified more than 1 risk allele within SNCA and GBA.

Copyright © 2012 American Neurological Association.
PMID: 22451204 [PubMed - indexed for MEDLINE] PMCID: PMC3354734 [Available on 2013/3/1]

Libro Genética de la Enfermedad de Parkinson

Para que llegue a todos los interesados, comparto el libro en Google Drive.

Se puede descargar aquí en (pdf).