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1.  Lethal phenotype in conditional late-onset arginase 1 deficiency in the mouse 
Molecular genetics and metabolism  2013;110(3):222-230.
Human arginase deficiency is characterized by hyperargininemia and infrequent episodes of hyperammonemia, which lead to neurological impairment with spasticity, loss of ambulation, seizures, and severe mental and growth retardation; uncommonly, patients suffer early death from this disorder. In a murine targeted knockout model, onset of the phenotypic abnormality is heralded by weight loss at around day 15, and death occurs typically by postnatal day 17 with hyperargininemia and markedly elevated ammonia. This discrepancy between the more attenuated juvenile-onset human disease and the lethal neonatal murine model has remained suboptimal for studying and developing therapy for the more common presentation of argianse deficiency. These investigations aimed to address this issue by creating an adult conditional knockout mouse to determine whether later onset of arginase deficiency also resulted in lethality. Animal survival and ammonia levels, body weight, circulating amino acids, and tissue arginase levels were examined as outcome parameters after widespread Cre-recombinase activation in a conditional knockout model of arginase 1 deficiency. One hundred percent of adult female and 70 percent of adult male mice died an average of 21.0 and 21.6 days, respectively, after the initiation of tamoxifen administration. Animals demonstrated elevated circulating ammonia and arginine at the onset of phenotypic abnormalities. In addition, brain and liver amino acids demonstrated abnormalities. These studies demonstrate that (a) the absence of arginase in adult animals results in a disease profile (leading to death) similar to that of the targeted knockout and (b) the phenotypic abnormalities seen in the juvenile-onset model are not exclusive to the age of the animal but instead to the biochemistry of the disorder. This adult model will be useful for developing gene- and cell-based therapies for this disorder that will not limited by by the small animal size of neonatal therapy and for developing a better understanding of the characteristics of hyperargininemia.
doi:10.1016/j.ymgme.2013.06.020
PMCID: PMC3800271  PMID: 23920045
Arginase deficiency; Hyperargininemia; Conditional knockout; Animal model
2.  Promoter DNA methylation regulates progranulin expression and is altered in FTLD 
Background
Frontotemporal lobar degeneration (FTLD) is a heterogeneous group of neurodegenerative diseases associated with personality changes and progressive dementia. Loss-of-function mutations in the growth factor progranulin (GRN) cause autosomal dominant FTLD, but so far the pathomechanism of sporadic FTLD is unclear.
Results
We analyzed whether DNA methylation in the GRN core promoter restricts GRN expression and, thus, might promote FTLD in the absence of GRN mutations. GRN expression in human lymphoblast cell lines is negatively correlated with methylation at several CpG units within the GRN promoter. Chronic treatment with the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine (DAC) strongly induces GRN mRNA and protein levels. In a reporter assay, CpG methylation blocks transcriptional activity of the GRN core promoter. In brains of FTLD patients several CpG units in the GRN promoter are significantly hypermethylated compared to age-matched healthy controls, Alzheimer and Parkinson patients. These CpG motifs are critical for GRN promoter activity in reporter assays. Furthermore, DNA methyltransferase 3a (DNMT3a) is upregulated in FTLD patients and overexpression of DNMT3a reduces GRN promoter activity and expression.
Conclusion
These data suggest that altered DNA methylation is a novel pathomechanism for FTLD that is potentially amenable to targeted pharmacotherapy.
doi:10.1186/2051-5960-1-16
PMCID: PMC3893557  PMID: 24252647
5-aza-2′-deoxycytidine; DNA methylation; Epigenetics; FTLD; Progranulin
3.  Genetic and Clinical Features of Progranulin-Associated Frontotemporal Lobar Degeneration 
Archives of neurology  2011;68(4):488-497.
Objective
To assess the relative frequency of unique mutations and their associated characteristics in 97 individuals with mutations in progranulin (GRN), an important cause of frontotemporal lobar degeneration (FTLD).
Participants and Design
A 46-site International Frontotemporal Lobar Degeneration Collaboration was formed to collect cases of FTLD with TAR DNA-binding protein of 43-kDa (TDP-43)–positive inclusions (FTLD-TDP). We identified 97 individuals with FTLD-TDP with pathogenic GRN mutations (GRN+ FTLD-TDP), assessed their genetic and clinical characteristics, and compared them with 453 patients with FTLD-TDP in which GRN mutations were excluded (GRN− FTLD-TDP). No patients were known to be related. Neuropathologic characteristics were confirmed as FTLD-TDP in 79 of the 97 GRN+ FTLDTDP cases and all of the GRN− FTLD-TDP cases.
Results
Age at onset of FTLD was younger in patients with GRN+ FTLD-TDP vs GRN− FTLD-TDP (median, 58.0 vs 61.0 years; P<.001), as was age at death (median, 65.5 vs 69.0 years; P<.001). Concomitant motor neuron disease was much less common in GRN+ FTLDTDP vs GRN− FTLD-TDP (5.4% vs 26.3%; P<.001). Fifty different GRN mutations were observed, including 2 novel mutations: c.139delG (p.D47TfsX7) and c.378C>A (p.C126X). The 2 most common GRN mutations were c.1477C>T (p.R493X, found in 18 patients, representing 18.6% of GRN cases) and c.26C>A (p.A9D, found in 6 patients, representing 6.2% of cases). Patients with the c.1477C>T mutation shared a haplotype on chromosome 17; clinically, they resembled patients with other GRN mutations. Patients with the c.26C>A mutation appeared to have a younger age at onset of FTLD and at death and more parkinsonian features than those with other GRN mutations.
Conclusion
GRN+ FTLD-TDP differs in key features from GRN− FTLD-TDP.
doi:10.1001/archneurol.2011.53
PMCID: PMC3160280  PMID: 21482928
4.  Both common variations and rare non-synonymous substitutions and small insertion/deletions in CLU are associated with increased Alzheimer risk 
Background
We have followed-up on the recent genome-wide association (GWA) of the clusterin gene (CLU) with increased risk for Alzheimer disease (AD), by performing an unbiased resequencing of all CLU coding exons and regulatory regions in an extended Flanders-Belgian cohort of Caucasian AD patients and control individuals (n = 1930). Moreover, we have replicated genetic findings by targeted resequencing in independent Caucasian cohorts of French (n = 2182) and Canadian (n = 573) origin and by performing meta-analysis combining our data with previous genetic CLU screenings.
Results
In the Flanders-Belgian cohort, we identified significant clustering in exons 5-8 of rare genetic variations leading to non-synonymous substitutions and a 9-bp insertion/deletion affecting the CLU β-chain (p = 0.02). Replicating this observation by targeted resequencing of CLU exons 5-8 in 2 independent Caucasian cohorts of French and Canadian origin identified identical as well as novel non-synonymous substitutions and small insertion/deletions. A meta-analysis, combining the datasets of the 3 cohorts with published CLU sequencing data, confirmed that rare coding variations in the CLU β-chain were significantly enriched in AD patients (ORMH = 1.96 [95% CI = 1.18-3.25]; p = 0.009). Single nucleotide polymorphisms (SNPs) association analysis indicated the common AD risk association (GWA SNP rs11136000, p = 0.013) in the 3 combined datasets could not be explained by the presence of the rare coding variations we identified. Further, high-density SNP mapping in the CLU locus mapped the common association signal to a more 5' CLU region.
Conclusions
We identified a new genetic risk association of AD with rare coding CLU variations that is independent of the 5' common association signal identified in the GWA studies. At this stage the role of these coding variations and their likely effect on the β-chain domain and CLU protein functioning remains unclear and requires further studies.
doi:10.1186/1750-1326-7-3
PMCID: PMC3296573  PMID: 22248099
Alzheimer disease; clusterin gene (CLU); genomic resequencing; non-synonymous substitutions; insertions/deletions; β-chain domain; meta-analysis
5.  Common variants in ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease 
Hollingworth, Paul | Harold, Denise | Sims, Rebecca | Gerrish, Amy | Lambert, Jean-Charles | Carrasquillo, Minerva M | Abraham, Richard | Hamshere, Marian L | Pahwa, Jaspreet Singh | Moskvina, Valentina | Dowzell, Kimberley | Jones, Nicola | Stretton, Alexandra | Thomas, Charlene | Richards, Alex | Ivanov, Dobril | Widdowson, Caroline | Chapman, Jade | Lovestone, Simon | Powell, John | Proitsi, Petroula | Lupton, Michelle K | Brayne, Carol | Rubinsztein, David C | Gill, Michael | Lawlor, Brian | Lynch, Aoibhinn | Brown, Kristelle S | Passmore, Peter A | Craig, David | McGuinness, Bernadette | Todd, Stephen | Holmes, Clive | Mann, David | Smith, A David | Beaumont, Helen | Warden, Donald | Wilcock, Gordon | Love, Seth | Kehoe, Patrick G | Hooper, Nigel M | Vardy, Emma R. L. C. | Hardy, John | Mead, Simon | Fox, Nick C | Rossor, Martin | Collinge, John | Maier, Wolfgang | Jessen, Frank | Schürmann, Britta | Rüther, Eckart | Heun, Reiner | Kölsch, Heike | van den Bussche, Hendrik | Heuser, Isabella | Kornhuber, Johannes | Wiltfang, Jens | Dichgans, Martin | Frölich, Lutz | Hampel, Harald | Hüll, Michael | Gallacher, John | Rujescu, Dan | Giegling, Ina | Goate, Alison M | Kauwe, John S K | Cruchaga, Carlos | Nowotny, Petra | Morris, John C | Mayo, Kevin | Sleegers, Kristel | Bettens, Karolien | Engelborghs, Sebastiaan | De Deyn, Peter P | Van Broeckhoven, Christine | Livingston, Gill | Bass, Nicholas J | Gurling, Hugh | McQuillin, Andrew | Gwilliam, Rhian | Deloukas, Panagiotis | Al-Chalabi, Ammar | Shaw, Christopher E | Tsolaki, Magda | Singleton, Andrew B | Guerreiro, Rita | Mühleisen, Thomas W | Nöthen, Markus M | Moebus, Susanne | Jöckel, Karl-Heinz | Klopp, Norman | Wichmann, H-Erich | Pankratz, V Shane | Sando, Sigrid B | Aasly, Jan O | Barcikowska, Maria | Wszolek, Zbigniew K | Dickson, Dennis W | Graff-Radford, Neill R | Petersen, Ronald C | van Duijn, Cornelia M | Breteler, Monique MB | Ikram, M Arfan | DeStefano, Anita L | Fitzpatrick, Annette L | Lopez, Oscar | Launer, Lenore J | Seshadri, Sudha | Berr, Claudine | Campion, Dominique | Epelbaum, Jacques | Dartigues, Jean-François | Tzourio, Christophe | Alpérovitch, Annick | Lathrop, Mark | Feulner, Thomas M | Friedrich, Patricia | Riehle, Caterina | Krawczak, Michael | Schreiber, Stefan | Mayhaus, Manuel | Nicolhaus, S | Wagenpfeil, Stefan | Steinberg, Stacy | Stefansson, Hreinn | Stefansson, Kari | Snædal, Jon | Björnsson, Sigurbjörn | Jonsson, Palmi V. | Chouraki, Vincent | Genier-Boley, Benjamin | Hiltunen, Mikko | Soininen, Hilkka | Combarros, Onofre | Zelenika, Diana | Delepine, Marc | Bullido, Maria J | Pasquier, Florence | Mateo, Ignacio | Frank-Garcia, Ana | Porcellini, Elisa | Hanon, Olivier | Coto, Eliecer | Alvarez, Victoria | Bosco, Paolo | Siciliano, Gabriele | Mancuso, Michelangelo | Panza, Francesco | Solfrizzi, Vincenzo | Nacmias, Benedetta | Sorbi, Sandro | Bossù, Paola | Piccardi, Paola | Arosio, Beatrice | Annoni, Giorgio | Seripa, Davide | Pilotto, Alberto | Scarpini, Elio | Galimberti, Daniela | Brice, Alexis | Hannequin, Didier | Licastro, Federico | Jones, Lesley | Holmans, Peter A | Jonsson, Thorlakur | Riemenschneider, Matthias | Morgan, Kevin | Younkin, Steven G | Owen, Michael J | O’Donovan, Michael | Amouyel, Philippe | Williams, Julie
Nature genetics  2011;43(5):429-435.
We sought to identify new susceptibility loci for Alzheimer’s disease (AD) through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer’s Disease Genetic Consortium (ADGC). First, we undertook a combined analysis of four genome-wide association datasets (Stage 1) and identified 10 novel variants with P≤1×10−5. These were tested for association in an independent sample (Stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (Stage 3). Meta-analyses of all data provide compelling evidence that ABCA7 (meta-P 4.5×10−17; including ADGC meta-P=5.0×10−21) and the MS4A gene cluster (rs610932, meta-P=1.8×10−14; including ADGC meta-P=1.2×10−16; rs670139, meta-P=1.4×10−9; including ADGC meta-P=1.1×10−10) are novel susceptibility loci for AD. Second, we observed independent evidence for association for three suggestive loci reported by the ADGC GWAS, which when combined shows genome-wide significance: CD2AP (GERAD+ P=8.0×10−4; including ADGC meta-P=8.6×10−9), CD33 (GERAD+ P=2.2×10−4; including ADGC meta-P=1.6×10−9) and EPHA1 (GERAD+ P=3.4×10−4; including ADGC meta-P=6.0×10−10). These findings support five novel susceptibility genes for AD.
doi:10.1038/ng.803
PMCID: PMC3084173  PMID: 21460840
6.  Sinus Sigmoideus Thrombosis Secondary to Graves' Disease: A Case Description 
Case Reports in Neurology  2011;3(3):203-209.
Cerebral venous thrombosis (CVT) is a distinct cerebrovascular condition that represents 0.5-1% of all strokes in the general population. Because of its procoagulant and antifibrinolytic effects [Horne et al.: J Clin Endocrinol Metab 2004;89:4469-4473], hyperthyroidism has been proposed as a predisposing factor for CVT [Saposnik et al.: Stroke 2011;42:1158-1192]. For the first time, we describe a 22-year-old right-handed woman with a sinus sigmoideus thrombosis due to Graves' disease. Although subclinical hyperthyroidism had been detected 2 years before the onset of neurological symptoms, she did not receive any medical follow-up. Early recognition, diagnosis and treatment are of crucial importance, as Graves' disease is a risk factor for CVT and stroke.
doi:10.1159/000331448
PMCID: PMC3214671  PMID: 22114580
Graves' disease; Cerebral venous thrombosis; Subclinical hyperthyroidism; Sinus sigmoideus thrombosis
7.  TMEM106B is associated with frontotemporal lobar degeneration in a clinically diagnosed patient cohort 
Brain  2011;134(3):808-815.
In a genome-wide association study of frontotemporal lobar degeneration with pathological inclusions of TAR DNA-binding protein, significant association was obtained with three single nucleotide polymorphisms at 7p21.3, in a region encompassing the gene TMEM106B. This study also suggested a potential modifying effect of TMEM106B on disease since the association was strongest in progranulin mutation carriers. Further, the risk effect seemed to correlate with increased TMEM106B expression in patients. In the present study, we sought to replicate these three findings using an independent Flanders–Belgian cohort of primarily clinically diagnosed patients with frontotemporal lobar degeneration (n = 288). We were able to confirm the association with TMEM106B with a P-value of 0.008 for rs1990622, the top marker from the genome-wide association study [odds ratio 0.75 (95% confidence interval 0.61–0.93)]. Further, high-density single nucleotide polymorphism mapping suggested that the association was solely driven by the gene TMEM106B. Homozygous carriers of the TMEM106B protective alleles had a 50% reduced risk of developing frontotemporal lobar degeneration. However, we were unable to detect a modifying effect of the TMEM106B single nucleotide polymorphisms on onset age in progranulin mutation carriers belonging to an extended, clinical and pathological well-documented founder family segregating a progranulin null mutation. Also, we could not observe significant differences in messenger RNA expression between patients and control individuals in lymphoblast cell lines and in brain frontal cortex. In conclusion, we replicated the genetic TMEM106B association in a primarily clinically diagnosed cohort of patients with frontotemporal lobar degeneration from Flanders–Belgium. Additional studies are needed to unravel the molecular role of TMEM106B in disease onset and pathogenesis.
doi:10.1093/brain/awr007
PMCID: PMC3044834  PMID: 21354975
frontotemporal lobar degeneration; TMEM106B; genetic association; risk factor
8.  FUS pathology defines the majority of tau- and TDP-43-negative frontotemporal lobar degeneration 
Acta neuropathologica  2010;120(1):33-41.
Through an international consortium, we have collected 37 tau- and TAR DNA-binding protein 43 (TDP-43)-negative frontotemporal lobar degeneration (FTLD) cases, and present here the first comprehensive analysis of these cases in terms of neuropathology, genetics, demographics and clinical data. 92% (34/37) had fused in sarcoma (FUS) protein pathology, indicating that FTLD-FUS is an important FTLD subtype. This FTLD-FUS collection specifically focussed on aFTLD-U cases, one of three recently defined subtypes of FTLD-FUS. The aFTLD-U subtype of FTLD-FUS is characterised clinically by behavioural variant frontotemporal dementia (bvFTD) and has a particularly young age of onset with a mean of 41 years. Further, this subtype had a high prevalence of psychotic symptoms (36% of cases) and low prevalence of motor symptoms (3% of cases). We did not find FUS mutations in any aFTLD-U case. To date, the only subtype of cases reported to have ubiquitin-positive but tau-, TDP-43- and FUS-negative pathology, termed FTLD-UPS, is the result of charged multivesicular body protein 2B gene (CHMP2B) mutation. We identified three FTLD-UPS cases, which are negative for CHMP2B mutation, suggesting that the full complement of FTLD pathologies is yet to be elucidated.
doi:10.1007/s00401-010-0698-6
PMCID: PMC2887939  PMID: 20490813
FTLD; FUS; FTLD-UPS; Frontotemporal; FTD
9.  FUS pathology defines the majority of tau- and TDP-43-negative frontotemporal lobar degeneration 
Acta Neuropathologica  2010;120(1):33-41.
Through an international consortium, we have collected 37 tau- and TAR DNA-binding protein 43 (TDP-43)-negative frontotemporal lobar degeneration (FTLD) cases, and present here the first comprehensive analysis of these cases in terms of neuropathology, genetics, demographics and clinical data. 92% (34/37) had fused in sarcoma (FUS) protein pathology, indicating that FTLD-FUS is an important FTLD subtype. This FTLD-FUS collection specifically focussed on aFTLD-U cases, one of three recently defined subtypes of FTLD-FUS. The aFTLD-U subtype of FTLD-FUS is characterised clinically by behavioural variant frontotemporal dementia (bvFTD) and has a particularly young age of onset with a mean of 41 years. Further, this subtype had a high prevalence of psychotic symptoms (36% of cases) and low prevalence of motor symptoms (3% of cases). We did not find FUS mutations in any aFTLD-U case. To date, the only subtype of cases reported to have ubiquitin-positive but tau-, TDP-43- and FUS-negative pathology, termed FTLD-UPS, is the result of charged multivesicular body protein 2B gene (CHMP2B) mutation. We identified three FTLD-UPS cases, which are negative for CHMP2B mutation, suggesting that the full complement of FTLD pathologies is yet to be elucidated.
doi:10.1007/s00401-010-0698-6
PMCID: PMC2887939  PMID: 20490813
FTLD; FUS; FTLD-UPS; Frontotemporal; FTD
10.  Large-scale replication and heterogeneity in Parkinson disease genetic loci 
Sharma, Manu | Ioannidis, John P.A. | Aasly, Jan O. | Annesi, Grazia | Brice, Alexis | Van Broeckhoven, Christine | Bertram, Lars | Bozi, Maria | Crosiers, David | Clarke, Carl | Facheris, Maurizio | Farrer, Matthew | Garraux, Gaetan | Gispert, Suzana | Auburger, Georg | Vilariño-Güell, Carles | Hadjigeorgiou, Georgios M. | Hicks, Andrew A. | Hattori, Nobutaka | Jeon, Beom | Lesage, Suzanne | Lill, Christina M. | Lin, Juei-Jueng | Lynch, Timothy | Lichtner, Peter | Lang, Anthony E. | Mok, Vincent | Jasinska-Myga, Barbara | Mellick, George D. | Morrison, Karen E. | Opala, Grzegorz | Pramstaller, Peter P. | Pichler, Irene | Park, Sung Sup | Quattrone, Aldo | Rogaeva, Ekaterina | Ross, Owen A. | Stefanis, Leonidas | Stockton, Joanne D. | Satake, Wataru | Silburn, Peter A. | Theuns, Jessie | Tan, Eng-King | Toda, Tatsushi | Tomiyama, Hiroyuki | Uitti, Ryan J. | Wirdefeldt, Karin | Wszolek, Zbigniew | Xiromerisiou, Georgia | Yueh, Kuo-Chu | Zhao, Yi | Gasser, Thomas | Maraganore, Demetrius | Krüger, Rejko | Boyle, R.S | Sellbach, A | O'Sullivan, J.D. | Sutherland, G.T. | Siebert, G.A | Dissanayaka, N.N.W | Van Broeckhoven, Christine | Theuns, Jessie | Crosiers, David | Pickut, Barbara | Engelborghs, Sebastiaan | Meeus, Bram | De Deyn, Peter P. | Cras, Patrick | Rogaeva, Ekaterina | Lang, Anthony E | Agid, Y | Anheim, M | Bonnet, A-M | Borg, M | Brice, A | Broussolle, E | Corvol, JC | Damier, P | Destée, A | Dürr, A | Durif, F | Lesage, S | Lohmann, E | Pollak, P | Rascol, O | Tison, F | Tranchant, C | Viallet, F | Vidailhet, M | Tzourio, Christophe | Amouyel, Philippe | Loriot, Marie-Anne | Mutez, Eugénie | Duflot, Aurélie | Legendre, Jean-Philippe | Waucquier, Nawal | Gasser, Thomas | Riess, Olaf | Berg, Daniela | Schulte, Claudia | Klein, Christine | Djarmati, Ana | Hagenah, Johann | Lohmann, Katja | Auburger, Georg | Hilker, Rüdiger | van de Loo, Simone | Dardiotis, Efthimios | Tsimourtou, Vaia | Ralli, Styliani | Kountra, Persa | Patramani, Gianna | Vogiatzi, Cristina | Hattori, Nobutaka | Tomiyama, Hiroyuki | Funayama, Manabu | Yoshino, Hiroyo | Li, Yuanzhe | Imamichi, Yoko | Toda, Tatsushi | Satake, Wataru | Lynch, Tim | Gibson, J. Mark | Valente, Enza Maria | Ferraris, Alessandro | Dallapiccola, Bruno | Ialongo, Tamara | Brighina, Laura | Corradi, Barbara | Piolti, Roberto | Tarantino, Patrizia | Annesi, Ferdinanda | Jeon, Beom S. | Park, Sung-Sup | Aasly, J | Opala, Grzegorz | Jasinska-Myga, Barbara | Klodowska-Duda, Gabriela | Boczarska-Jedynak, Magdalena | Tan, Eng King | Belin, Andrea Carmine | Olson, Lars | Galter, Dagmar | Westerlund, Marie | Sydow, Olof | Nilsson, Christer | Puschmann, Andreas | Lin, JJ | Maraganore, Demetrius M. | Ahlskog, J, Eric | de Andrade, Mariza | Lesnick, Timothy G. | Rocca, Walter A. | Checkoway, Harvey | Ross, Owen A | Wszolek, Zbigniew K. | Uitti, Ryan J.
Neurology  2012;79(7):659-667.
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 (I2 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. Neurology® 2012;79:659–667
doi:10.1212/WNL.0b013e318264e353
PMCID: PMC3414661  PMID: 22786590

Results 1-10 (10)