TY  - JOUR
AB  - BACKGROUND AND OBJECTIVES: The role of body mass index (BMI) in Parkinson disease (PD) is unclear. Based on the Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in PD (Courage-PD) consortium, we used 2-sample Mendelian randomization (MR) to replicate a previously reported inverse association of genetically predicted BMI with PD and investigated whether findings were robust in analyses addressing the potential for survival and incidence-prevalence biases. We also examined whether the BMI-PD relation is bidirectional by performing a reverse MR. METHODS: We used summary statistics from a genome-wide association study (GWAS) to extract the association of 501 single-nucleotide polymorphisms (SNPs) with BMI and from the Courage-PD and international Parkinson Disease Genomics Consortium (iPDGC) to estimate their association with PD. Analyses are based on participants of European ancestry. We used the inverse-weighted method to compute odds ratios (ORIVW per 4.8 kg/m2 [95% CI]) of PD and additional pleiotropy robust methods. We performed analyses stratified by age, disease duration, and sex. For reverse MR, we used SNPs associated with PD from 2 iPDGC GWAS to assess the effect of genetic liability toward PD on BMI. RESULTS: Summary statistics for BMI are based on 806,834 participants (54% women). Summary statistics for PD are based on 8,919 (40% women) cases and 7,600 (55% women) controls from Courage-PD, and 19,438 (38% women) cases and 24,388 (51% women) controls from iPDGC. In Courage-PD, we found an inverse association between genetically predicted BMI and PD (ORIVW 0.82 [0.70-0.97], p = 0.012) without evidence for pleiotropy. This association tended to be stronger in younger participants (≤67 years, ORIVW 0.71 [0.55-0.92]) and cases with shorter disease duration (≤7 years, ORIVW 0.75 [0.62-0.91]). In pooled Courage-PD + iPDGC analyses, the association was stronger in women (ORIVW 0.85 [0.74-0.99], p = 0.032) than men (ORIVW 0.92 [0.80-1.04], p = 0.18), but the interaction was not statistically significant (p-interaction = 0.48). In reverse MR, there was evidence for pleiotropy, but pleiotropy robust methods showed a significant inverse association. DISCUSSION: Using an independent data set (Courage-PD), we replicate an inverse association of genetically predicted BMI with PD, not explained by survival or incidence-prevalence biases. Moreover, reverse MR analyses support an inverse association between genetic liability toward PD and BMI, in favor of a bidirectional relation.
AU  - Domenighetti, C.*
AU  - Sugier, P.E.*
AU  - Ashok Kumar Sreelatha, A.*
AU  - Schulte, C.*
AU  - Grover, S.*
AU  - Portugal, B.*
AU  - Lee, P.C.*
AU  - May, P.*
AU  - Bobbili, D.R.*
AU  - Radivojkov-Blagojevic, M.
AU  - Lichtner, P.
AU  - Singleton, A.B.*
AU  - Hernandez, D.*
AU  - Edsall, C.*
AU  - Mellick, G.D.*
AU  - Zimprich, A.A.*
AU  - Pirker, W.*
AU  - Rogaeva, E.A.*
AU  - Lang, A.E.*
AU  - Kõks, S.*
AU  - Taba, P.*
AU  - Lesage, S.*
AU  - Brice, A.*
AU  - Corvol, J.C.*
AU  - Chartier-Harlin, M.C.*
AU  - Mutez, E.*
AU  - Brockmann, K.*
AU  - Deutschländer, A.B.*
AU  - Hadjigeorgiou, G.M.*
AU  - Dardiotis, E.*
AU  - Stefanis, L.*
AU  - Simitsi, A.M.*
AU  - Valente, E.M.*
AU  - Petrucci, S.*
AU  - Straniero, L.*
AU  - Zecchinelli, A.L.*
AU  - Pezzoli, G.*
AU  - Brighina, L.*
AU  - Ferrarese, C.*
AU  - Annesi, G.*
AU  - Quattrone, A.*
AU  - Gagliardi, M.*
AU  - Matsuo, H.*
AU  - Nakayama, A.*
AU  - Hattori, N.*
AU  - Nishioka, K.*
AU  - Chung, S.J.*
AU  - Kim, Y.J.*
AU  - Kolber, P.*
AU  - van de Warrenburg, B.P.C.*
AU  - Bloem, B.R.*
AU  - Toft, M.*
AU  - Pihlstrøm, L.*
AU  - Correia Guedes, L.*
AU  - Ferreira, J.J.*
AU  - Bardien, S.*
AU  - Carr, J.*
AU  - Tolosa, E.*
AU  - Ezquerra, M.*
AU  - Pastor, P.*
AU  - Diez-Fairen, M.*
AU  - Wirdefeldt, K.*
AU  - Pedersen, N.L.*
AU  - Ran, C.*
AU  - Belin, A.C.*
AU  - Puschmann, A.*
AU  - Hellberg, C.*
AU  - Clarke, C.E.*
AU  - Morrison, K.E.*
AU  - Tan, M.M.*
AU  - Krainc, D.*
AU  - Burbulla, L.F.*
AU  - Farrer, M.*
AU  - Kruger, R.*
AU  - Gasser, T.*
AU  - Sharma, M.*
AU  - Elbaz, A.*
C1  - 71079
C2  - 55961
CY  - Two Commerce Sq, 2001 Market St, Philadelphia, Pa 19103 Usa
TI  - Association of body mass index and parkinson disease: A bidirectional mendelian randomization study.
JO  - Neurology
VL  - 103
IS  - 3
PB  - Lippincott Williams & Wilkins
PY  - 2024
SN  - 0028-3878
ER  - 

TY  - JOUR
AB  - BACKGROUND AND OBJECTIVES: Considerable heterogeneity exists in the literature concerning genetic determinants of the age of onset (AAO) of Parkinson's disease (PD), which could be attributed to lack of well-powered replication cohorts. The previous largest GWAS identified SNCA and TMEM175 loci on chromosome (Chr) 4 with a significant influence on AAO of PD, these have not been independently replicated. The present study aims to conduct a meta-analysis of GWAS of PD AAO and validate previously observed findings in worldwide populations. METHODS: A meta-analysis was performed on PD AAO GWAS of 30 populations of predominantly European ancestry from the Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease (COURAGE-PD) consortium. This was followed up by combining our study with the largest publicly available European ancestry dataset compiled by the International Parkinson disease Genomics Consortium (IPDGC). RESULTS: The COURAGE-PD included a cohort of 8,535 patients with PD (91.9%: Europeans, 9.1%: East-Asians). The average AAO in the COURAGE-PD dataset was 58.9 years (SD=11.6), with an under-representation of females (40.2%). The heritability estimate for AAO in COURAGE-PD was 0.083 (SE=0.057). None of the loci reached genome-wide significance (P<5x10-8). Nevertheless, the COURAGE-PD dataset confirmed the role of the previously published TMEM175 variant as genetic determinant of AAO of PD with Bonferroni-corrected nominal levels of significance (P<0.025): (rs34311866:β(SE)COURAGE=0.477(0.203), PCOURAGE=0.0185). The subsequent meta-analysis of COURAGE-PD and IPDGC datasets (Ntotal=25,950) led to the identification of two genome-wide significant association signals on Chr 4, including the previously reported SNCA locus (rs983361:β(SE)COURAGE+IPDGC=0.720(0.122), PCOURAGE+IPDGC=3.13x10-9) and a novel BST1 locus (rs4698412:β(SE)COURAGE+IPDGC=-0.526(0.096), PCOURAGE+IPDGC=4.41x10-8). DISCUSSION: Our study further refines the genetic architecture of Chr 4 underlying the AAO of the PD phenotype through the identification of BST1 as a novel AAO PD locus. These findings open a new direction for the development of treatments to delay the onset of PD.
AU  - Grover, S.*
AU  - Ashwin, A.K.S.*
AU  - Pihlstrom, L.*
AU  - Domenighetti, C.*
AU  - Schulte, C.*
AU  - Sugier, P.E.*
AU  - Radivojkov-Blagojevic, M.
AU  - Lichtner, P.
AU  - Mohamed, O.*
AU  - Portugal, B.*
AU  - Landoulsi, Z.*
AU  - May, P.*
AU  - Bobbili, D.R.*
AU  - Edsall, C.*
AU  - Bartusch, F.*
AU  - Hanussek, M.*
AU  - Krüger, J.*
AU  - Hernandez, D.G.*
AU  - Blauwendraat, C.*
AU  - Mellick, G.D.*
AU  - Zimprich, A.*
AU  - Pirker, W.*
AU  - Tan, M.*
AU  - Rogaeva, E.*
AU  - Lang, A.*
AU  - Kõks, S.*
AU  - Taba, P.*
AU  - Lesage, S.*
AU  - Brice, A.*
AU  - Corvol, J.C.*
AU  - Chartier-Harlin, M.C.*
AU  - Mutez, E.*
AU  - Brockmann, K.*
AU  - Deutschländer, A.B.*
AU  - Hadjigeorgiou, G.M.*
AU  - Dardiotis, E.*
AU  - Stefanis, L.*
AU  - Simitsi, A.M.*
AU  - Valente, E.M.*
AU  - Petrucci, S.*
AU  - Straniero, L.*
AU  - Zecchinelli, A.*
AU  - Pezzoli, G.*
AU  - Brighina, L.*
AU  - Ferrarese, C.*
AU  - Annesi, G.*
AU  - Quattrone, A.*
AU  - Gagliardi, M.*
AU  - Burbulla, L.F.*
AU  - Matsuo, H.*
AU  - Kawamura, Y.*
AU  - Hattori, N.*
AU  - Nishioka, K.*
AU  - Chung, S.J.*
AU  - Kim, Y.J.*
AU  - Pavelka, L.*
AU  - van de Warrenburg, B.P.*
AU  - Bloem, B.R.*
AU  - Singleton, A.B.*
AU  - Aasly, J.O.*
AU  - Toft, M.F.*
AU  - Guedes, L.C.*
AU  - Ferreira, J.J.*
AU  - Bardien, S.*
AU  - Carr, J.*
AU  - Tolosa, E.*
AU  - Ezquerra, M.*
AU  - Pastor, P.*
AU  - Diez-Fairen, M.*
AU  - Wirdefeldt, K.*
AU  - Pedersen, N.L.*
AU  - Ran, C.*
AU  - Belin, A.C.*
AU  - Puschmann, A.J.*
AU  - Hellberg, C.*
AU  - Clarke, C.E.*
AU  - Morrison, K.E.*
AU  - Krainc, D.*
AU  - Farrer, M.J.*
AU  - Kruger, R.*
AU  - Elbaz, A.*
AU  - Gasser, T.*
AU  - Sharma, M.*
C1  - 65479
C2  - 52320
SP  - e698-e710
TI  - Genome-wide association and meta-analysis of age-at-onset in parkinson disease: Evidence from COURAGE-PD consortium.
JO  - Neurology
VL  - 99
IS  - 7
PY  - 2022
SN  - 0028-3878
ER  - 

TY  - JOUR
AB  - BACKGROUND AND OBJECTIVES: Current genome-wide association studies of ischemic stroke have focused primarily on late onset disease. As a complement to these studies, we sought to identifythe contribution of common genetic variants to risk of early onset ischemic stroke. METHODS: We performed a meta-analysis of genome-wide association studies of early onset stroke (EOS), ages 18-59, using individual level data or summary statistics in 16,730 cases and 599,237 non-stroke controls obtained across 48 different studies. We further compared effect sizes at associated loci between EOS and late onset stroke (LOS) and compared polygenic risk scores for venous thromboembolism between EOS and LOS. RESULTS: We observed genome-wide significant associations of EOS with two variants in ABO, a known stroke locus. These variants tag blood subgroups O1 and A1, and the effect sizes of both variants were significantly larger in EOS compared to LOS. The odds ratio (OR) for rs529565, tagging O1, 0.88 (95% CI: 0.85-0.91) in EOS vs 0.96 (95% CI: 0.92-1.00) in LOS, and the OR for rs635634, tagging A1, was 1.16 (1.11-1.21) for EOS vs 1.05 (0.99-1.11) in LOS; p-values for interaction = 0.001 and 0.005, respectively. Using polygenic risk scores, we observed that greater genetic risk for venous thromboembolism, another prothrombotic condition, was more strongly associated with EOS compared to LOS (p=0.008). DISCUSSION: The ABO locus, genetically predicted blood group A, and higher genetic propensity for venous thrombosis are more strongly associated with EOS than with LOS, supporting a stronger role of prothrombotic factors in EOS.
AU  - Jaworek, T.*
AU  - Xu, H.*
AU  - Gaynor, B.J.*
AU  - Cole, J.W.*
AU  - Rannikmäe, K.*
AU  - Stanne, T.M.*
AU  - Tomppo, L.*
AU  - Abedi, V.*
AU  - Amouyel, P.*
AU  - Armstrong, N.D.*
AU  - Attia, J.*
AU  - Bell, S.*
AU  - Benavente, O.R.*
AU  - Boncoraglio, G.B.*
AU  - Butterworth, A.*
AU  - Cárcel-Márquez, J.*
AU  - Chen, Z.*
AU  - Chong, M.*
AU  - Cruchaga, C.*
AU  - Cushman, M.*
AU  - Danesh, J.*
AU  - Debette, S.*
AU  - Duggan, D.J.*
AU  - Durda, J.P.*
AU  - Engström, G.*
AU  - Enzinger, C.*
AU  - Faul, J.D.*
AU  - Fecteau, N.S.*
AU  - Fernandez-Cadenas, I.*
AU  - Gieger, C.
AU  - Giese, A.K.*
AU  - Grewal, R.P.*
AU  - Grittner, U.*
AU  - Havulinna, A.S.*
AU  - Heitsch, L.*
AU  - Hochberg, M.C.*
AU  - Holliday, E.*
AU  - Hu, J.*
AU  - Ilinca, A.*
AU  - Irvin, M.R.*
AU  - Jackson, R.D.*
AU  - Jacob, M.A.*
AU  - Janssen, R.R.*
AU  - Jimenez-Conde, J.*
AU  - Johnson, J.A.*
AU  - Kamatani, Y.*
AU  - Kardia, S.L.*
AU  - Koido, M.*
AU  - Kubo, M.*
AU  - Lange, L.*
AU  - Lee, J.M.*
AU  - Lemmens, R.*
AU  - Levi, C.R.*
AU  - Li, J.*
AU  - Li, L.*
AU  - Lin, K.*
AU  - Lopez, H.*
AU  - Luke, S.*
AU  - Maguire, J.*
AU  - McArdle, P.F.*
AU  - McDonough, C.W.*
AU  - Meschia, J.F.*
AU  - Metso, T.M.*
AU  - Müller-Nurasyid, M.
AU  - O'Connor, T.D.*
AU  - O'Donnell, M.*
AU  - Peddareddygari, L.R.*
AU  - Pera, J.*
AU  - Perry, J.A.*
AU  - Peters, A.
AU  - Putaala, J.*
AU  - Ray, D.W.*
AU  - Rexrode, K.*
AU  - Ribasés, M.*
AU  - Rosand, J.*
AU  - Rothwell, P.M.*
AU  - Rundek, T.*
AU  - Ryan, K.A.*
AU  - Sacco, R.L.*
AU  - Salomaa, V.*
AU  - Sánchez-Mora, C.*
AU  - Schmidt, R.*
AU  - Sharma, P.*
AU  - Slowik, A.*
AU  - Smith, J.A.*
AU  - Smith, N.L.*
AU  - Wassertheil-Smoller, S.*
AU  - Soederholm, M.*
AU  - Stine, O.C.*
AU  - Strbian, D.*
AU  - Sudlow, C.L.*
AU  - Tatlisumak, T.*
AU  - Terao, C.*
AU  - Thijs, V.*
AU  - Torres-Aguila, N.P.*
AU  - Tregouet, D.A.*
AU  - Tuladhar, A.M.*
AU  - Veldink, J.H.*
AU  - Walters, R.G.*
AU  - Weir, D.R.*
AU  - Woo, D.*
AU  - Worrall, B.B.*
AU  - Hong, C.C.*
AU  - Ross, O.A.*
AU  - Zand, R.*
AU  - Leeuw, F.E.*
AU  - Lindgren, A.G.*
AU  - Paré, G.*
AU  - Anderson, C.D.*
AU  - Markus, H.S.*
AU  - Jern, C.*
AU  - Malik, R.*
AU  - Dichgans, M.*
AU  - Mitchell, B.D.*
AU  - Kittner, S.J.*
C1  - 66492
C2  - 52835
SP  - E1738-E1754
TI  - Contribution of common genetic variants to risk of early onset ischemic stroke.
JO  - Neurology
VL  - 99
IS  - 16
PY  - 2022
SN  - 0028-3878
ER  - 

TY  - JOUR
AB  - BACKGROUND AND OBJECTIVES: Human genetic studies support a key role of interleukin-6 (IL-6) in the pathogenesis of ischemic stroke. Still, there are only limited data from observational studies exploring circulating IL-6 levels as a risk factor for ischemic stroke. Here, we set out to perform a systematic review and meta-analysis of aggregate data on cohort studies to determine the magnitude and shape of the association between circulating IL-6 levels and risk of incident ischemic stroke in the general population. METHODS: Following the PRISMA guidelines, we systematically screened the PubMed search engine from inception to March 2021 for population-based prospective cohort studies exploring the association between circulating IL-6 levels and risk of incident ischemic stroke. We pooled association estimates for ischemic stroke risk with random-effects models and explored non-linear effects in dose-response meta-analyses. Risk of bias was assessed with the Newcastle-Ottawa scale (NOS). We used funnel plots and trim-to-fill analyses to assess publication bias. RESULTS: We identified 11 studies (n=27,411 individuals; 2,669 stroke events) meeting our eligibility criteria. Mean age of all included participants was 60.5 years and 54.8% were females. Overall, quality of the included studies was high (median 8 out of 9 NOS points, interquartile range 7 to 9). In meta-analyses, 1-standard deviation increment in circulating log-transformed IL-6 levels was associated with a 19% increase in risk of incident ischemic stroke over a mean follow-up of 12.4 years (RR 1.19; 95% CI 1.10 to 1.28). A dose-response meta-analysis showed a linear association between circulating IL-6 levels and ischemic stroke risk. There was only moderate heterogeneity and the results were consistent in sensitivity analyses restricted to studies of low risk of bias and studies fully adjusting for demographic and vascular risk factors. The results also remained stable following adjustment for publication bias. DISCUSSION: Higher circulating IL-6 levels in community-dwelling individuals are associated with higher long-term risk of incident ischemic stroke in a linear pattern and independently of conventional vascular risk factors. Along with findings from genetic studies and clinical trials, these results provide additional support for a key role of IL-6 signaling in ischemic stroke.
AU  - Papadopoulos, A.*
AU  - Palaiopanos, K.*
AU  - Björkbacka, H.*
AU  - Peters, A.
AU  - de Lemos, J.A.*
AU  - Seshadri, S.*
AU  - Dichgans, M.*
AU  - Georgakis, M.K.*
C1  - 64022
C2  - 51698
CY  - Two Commerce Sq, 2001 Market St, Philadelphia, Pa 19103 Usa
SP  - e1002-e1012
TI  - Circulating interleukin-6 levels and incident ischemic stroke: A systematic review and meta-analysis of prospective studies
JO  - Neurology
VL  - 98
IS  - 10
PB  - Lippincott Williams & Wilkins
PY  - 2022
SN  - 0028-3878
ER  - 

TY  - JOUR
AB  - OBJECTIVE: We sought to identify an abbreviated test of impaired olfaction, amenable for use in busy clinical environments in prodromal (isolated REM sleep Behavior Disorder (iRBD)) and manifest Parkinson's disease (PD). METHODS: 890 PD and 313 control participants in the Discovery cohort study underwent Sniffin' stick odour identification assessment. Random forests were initially trained to distinguish individuals with poor (functional anosmia/hyposmia) and good (normosmia/super-smeller) smell ability using all 16 Sniffin' sticks. Models were retrained using the top 3 sticks ranked by order of predictor importance. One randomly selected 3-stick model was tested in a second independent PD dataset (n=452) and in two iRBD datasets (Discovery n=241; Marburg n=37) before being compared to previously described abbreviated Sniffin' stick combinations. RESULTS: In differentiating poor from good smell ability, the overall area under the curve (AUC) value associated with the top 3 sticks (Anise/Licorice/Banana) was 0.95 in the development dataset (sensitivity:90%, specificity:92%, positive predictive value:92%, negative predictive value:90%). Internal and external validation confirmed AUCs≥0.90. The combination of 3-stick model determined poor smell and an RBD screening questionnaire score of ≥5, separated iRBD from controls with a sensitivity, specificity, PPV and NPV of 65%, 100%, 100% and 30%. CONCLUSIONS: Our 3-Sniffin'-stick model holds potential utility as a brief screening test in the stratification of individuals with PD and iRBD according to olfactory dysfunction. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that a 3-Sniffin'-stick model distinguishes individuals with poor and good smell ability and can be used to screen for individuals with iRBD.
AU  - Lo, C.*
AU  - Arora, S.*
AU  - Ben-Shlomo, Y.*
AU  - Barber, T.R.*
AU  - Lawton, M.*
AU  - Klein, J.C.*
AU  - Kanavou, S.*
AU  - Janzen, A.*
AU  - Sittig, E.*
AU  - Oertel, W.H.
AU  - Grosset, D.*
AU  - Hu, M.T.*
C1  - 61479
C2  - 50283
CY  - Two Commerce Sq, 2001 Market St, Philadelphia, Pa 19103 Usa
SP  - e2016-e2027
TI  - Olfactory testing in Parkinson's Disease & REM behavior disorder: A machine learning approach.
JO  - Neurology
VL  - 96
IS  - 15
PB  - Lippincott Williams & Wilkins
PY  - 2021
SN  - 0028-3878
ER  - 

TY  - JOUR
AB  - Objective Evidence from observational studies for the effect of physical activity on the risk of Alzheimer disease (AD) is inconclusive. We performed a 2-sample mendelian randomization analysis to examine whether physical activity is protective for AD. Methods Summary data of genome-wide association studies on physical activity and AD were used. The primary study population included 21,982 patients with AD and 41,944 cognitively normal controls. Eight single nucleotide polymorphisms (SNPs) known atp< 5 x 10(-8)to be associated with average accelerations and 8 SNPs associated atp< 5 x 10(-7)with vigorous physical activity (fraction of accelerations >425 milligravities) served as instrumental variables. Results There was no association between genetically predicted average accelerations with the risk of AD (inverse variance weighted odds ratio [OR] per SD increment: 1.03, 95% confidence interval 0.97-1.10,p= 0.332). Genetic liability for fraction of accelerations >425 milligravities was unrelated to AD risk. Conclusion The present study does not support a causal association between physical activity and risk of AD.
AU  - Baumeister, S.
AU  - Karch, A.*
AU  - Bahls, M.*
AU  - Teumer, A.*
AU  - Leitzmann, M.F.*
AU  - Baurecht, H.*
C1  - 59700
C2  - 48934
CY  - Two Commerce Sq, 2001 Market St, Philadelphia, Pa 19103 Usa
SP  - E1897-E1905
TI  - Physical activity and risk of Alzheimer disease A 2-sample mendelian randomization study.
JO  - Neurology
VL  - 95
IS  - 13
PB  - Lippincott Williams & Wilkins
PY  - 2020
SN  - 0028-3878
ER  - 

TY  - JOUR
AB  - ObjectiveTo investigate the association of triglyceride (TG) principal component scores with Alzheimer disease (AD) and the amyloid, tau, neurodegeneration, and cerebrovascular disease (A/T/N/V) biomarkers for AD.MethodsSerum levels of 84 TG species were measured with untargeted lipid profiling of 689 participants from the Alzheimer's Disease Neuroimaging Initiative cohort, including 190 cognitively normal older adults (CN), 339 with mild cognitive impairment (MCI), and 160 with AD. Principal component analysis with factor rotation was used for dimension reduction of TG species. Differences in principal components between diagnostic groups and associations between principal components and AD biomarkers (including CSF, MRI and [F-18]fluorodeoxyglucose-PET) were assessed with a generalized linear model approach. In both cases, the Bonferroni method of adjustment was used to correct for multiple comparisons.ResultsThe 84 TGs yielded 9 principal components, 2 of which, consisting of long-chain, polyunsaturated fatty acid-containing TGs (PUTGs), were significantly associated with MCI and AD. Lower levels of PUTGs were observed in MCI and AD compared to CN. PUTG principal component scores were also significantly associated with hippocampal volume and entorhinal cortical thickness. In participants carrying the APOE epsilon 4 allele, these principal components were significantly associated with CSF beta -amyloid(1-42) values and entorhinal cortical thickness.ConclusionThis study shows that PUTG component scores were significantly associated with diagnostic group and AD biomarkers, a finding that was more pronounced in APOE epsilon 4 carriers. Replication in independent larger studies and longitudinal follow-up are warranted.
AU  - Bernath, M.M.*
AU  - Bhattacharyya, S.*
AU  - Nho, K.*
AU  - Barupal, D.K.*
AU  - Fiehn, O.*
AU  - Baillie, R.*
AU  - Risacher, S.L.*
AU  - Arnold, M.
AU  - Jacobson, T.*
AU  - Trojanowski, J.Q.*
AU  - Shaw, L.M.*
AU  - Weiner, M.W.*
AU  - Doraiswamy, P.M.*
AU  - Kaddurah-Daouk, R.*
AU  - Saykin, A.J.*
C1  - 59205
C2  - 48728
CY  - Two Commerce Sq, 2001 Market St, Philadelphia, Pa 19103 Usa
SP  - E2088-E2098
TI  - Serum triglycerides in Alzheimer disease: Relation to neuroimaging and CSF biomarkers.
JO  - Neurology
VL  - 94
IS  - 20
PB  - Lippincott Williams & Wilkins
PY  - 2020
SN  - 0028-3878
ER  - 

TY  - JOUR
AB  - OBJECTIVE: To test the hypothesis that monogenic neuropathies such as Charcot-Marie-Tooth disease (CMT) contribute to frequent but often unexplained neuropathies in the elderly, we performed genetic analysis of 230 patients with unexplained axonal neuropathies and disease onset ≥35 years. METHODS: We recruited patients, collected clinical data and conducted whole-exome sequencing (WES, n = 126) and MME single-gene sequencing (n = 104). We further queried WES repositories for MME variants and measured blood levels of the MME-encoded protein neprilysin. RESULTS: In the WES cohort, the overall detection rate for assumed disease-causing variants in genes for CMT or other conditions associated with neuropathies was 18.3% (familial cases 26.4%, apparently sporadic cases 12.3%). MME was most frequently involved and accounted for 34.8% of genetically solved cases. The relevance of MME for late-onset neuropathies was further supported by detection of a comparable proportion of cases in an independent patient sample, preponderance of MME variants among patients compared to population frequencies, retrieval of additional late-onset neuropathy patients with MME variants from WES repositories, and low neprilysin levels in patients' blood samples. Transmission of MME variants was often consistent with an incompletely penetrant autosomal dominant trait and less frequently with autosomal recessive inheritance. CONCLUSIONS: A detectable fraction of unexplained late-onset axonal neuropathies is genetically determined, either by variants in CMT genes or genes involved in other conditions that affect the peripheral nerves and can mimic a CMT phenotype. MME variants can act as completely penetrant recessive alleles but also confer dominantly inherited susceptibility to axonal neuropathies in an aging population.
AU  - Senderek, J.*
AU  - Lassuthova, P.*
AU  - Kabzińska, D.*
AU  - Abreu, L.*
AU  - Baets, J.*
AU  - Beetz, C.*
AU  - Braathen, G.J.*
AU  - Brenner, D.*
AU  - Dalton, J.*
AU  - Dankwa, L.*
AU  - Deconinck, T.*
AU  - de Jonghe, P.*
AU  - Dräger, B.*
AU  - Eggermann, K.*
AU  - Ellis, M.*
AU  - Fischer, C.*
AU  - Stojkovic, T.*
AU  - Herrmann, D.N.*
AU  - Horvath, R.*
AU  - Høyer, H.*
AU  - Iglseder, S.*
AU  - Kennerson, M.*
AU  - Kinslechner, K.*
AU  - Kohler, J.N.*
AU  - Kurth, I.*
AU  - Laing, N.G.*
AU  - Lamont, P.J.*
AU  - Löscher, W.*
AU  - Ludolph, A.*
AU  - Marques, W.*
AU  - Nicholson, G.*
AU  - Ong, R.*
AU  - Petri, S.*
AU  - Ravenscroft, G.*
AU  - Rebelo, A.*
AU  - Ricci, G.*
AU  - Rudnik-Schöneborn, S.*
AU  - Schirmacher, A.*
AU  - Schlotter-Weigel, B.*
AU  - Schoels, L.*
AU  - Schüle, R.*
AU  - Synofzik, M.*
AU  - Francou, B.*
AU  - Strom, T.M.
AU  - Wagner, J.*
AU  - Walk, D.*
AU  - Wanschitz, J.*
AU  - Weinmann, D.*
AU  - Weishaupt, J.*
AU  - Wiessner, M.*
AU  - Windhager, R.*
AU  - Young, P.*
AU  - Züchner, S.*
AU  - Toegel, S.*
AU  - Seeman, P.*
AU  - Kochański, A.*
AU  - Auer-Grumbach, M.*
C1  - 60652
C2  - 49565
CY  - Two Commerce Sq, 2001 Market St, Philadelphia, Pa 19103 Usa
SP  - e3163-e3179
TI  - The genetic landscape of axonal neuropathies in the middle-aged and elderly: Focus on MME.
JO  - Neurology
VL  - 95
IS  - 24
PB  - Lippincott Williams & Wilkins
PY  - 2020
SN  - 0028-3878
ER  - 

TY  - JOUR
AB  - OBJECTIVE: To explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts. METHODS: We performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n = 20,949) from 5 ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6,862; 1,483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI. RESULTS: The mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, p = 1.77 × 10-8; and LINC00539/ZDHHC20, p = 5.82 × 10-9. Both have been associated with blood pressure (BP)-related phenotypes, but did not replicate in the smaller follow-up sample or show associations with related phenotypes. Age- and sex-adjusted associations with BI and SSBI were observed for BP traits (p value for BI, p [BI] = 9.38 × 10-25; p [SSBI] = 5.23 × 10-14 for hypertension), smoking (p [BI] = 4.4 × 10-10; p [SSBI] = 1.2 × 10-4), diabetes (p [BI] = 1.7 × 10-8; p [SSBI] = 2.8 × 10-3), previous cardiovascular disease (p [BI] = 1.0 × 10-18; p [SSBI] = 2.3 × 10-7), stroke (p [BI] = 3.9 × 10-69; p [SSBI] = 3.2 × 10-24), and MRI-defined white matter hyperintensity burden (p [BI] = 1.43 × 10-157; p [SSBI] = 3.16 × 10-106), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI (p ≤ 0.0022), without indication of directional pleiotropy. CONCLUSION: In this multiethnic GWAS meta-analysis, including over 20,000 population-based participants, we identified genetic risk loci for BI requiring validation once additional large datasets become available. High BP, including genetically determined, was the most significant modifiable, causal risk factor for BI.
AU  - Chauhan, G.*
AU  - Adams, H.H.H.*
AU  - Satizabal, C.L.*
AU  - Bis, J.C.*
AU  - Teumer, A.*
AU  - Sargurupremraj, M.*
AU  - Hofer, E.*
AU  - Trompet, S.*
AU  - Hilal, S.*
AU  - Smith, A.V.*
AU  - Jian, X.*
AU  - Malik, R.*
AU  - Traylor, M.*
AU  - Pulit, S.L.*
AU  - Amouyel, P.*
AU  - Mazoyer, B.*
AU  - Zhu, Y.C.*
AU  - Kaffashian, S.*
AU  - Schilling, S.*
AU  - Beecham, G.W.*
AU  - Montine, T.J.*
AU  - Schellenberg, G.D.*
AU  - Kjartansson, O.*
AU  - Guðnason, V.*
AU  - Knopman, D.S.*
AU  - Griswold, M.E.*
AU  - Windham, B.G.*
AU  - Gottesman, R.F.*
AU  - Mosley, T.H.*
AU  - Schmidt, R.*
AU  - Saba, Y.*
AU  - Schmidt, H.*
AU  - Takeuchi, F.*
AU  - Yamaguchi, S.*
AU  - Nabika, T.*
AU  - Kato, N.*
AU  - Rajan, K.B.*
AU  - Aggarwal, N.T.*
AU  - de Jager, P.L.*
AU  - Evans, D.A.*
AU  - Psaty, B.M.*
AU  - Rotter, J.I.*
AU  - Rice, K.*
AU  - Lopez, O.L.*
AU  - Liao, J.M.*
AU  - Chen, C.*
AU  - Cheng, C.Y.*
AU  - Wong, T.Y.*
AU  - Ikram, M.K.*
AU  - van der Lee, S.J.*
AU  - Amin, N.*
AU  - Chouraki, V.*
AU  - DeStefano, A.L.*
AU  - Aparicio, H.J.*
AU  - Romero, J.R.*
AU  - Maillard, P.*
AU  - Decarli, C.*
AU  - Wardlaw, J.M.*
AU  - Hernández, M.D.C.V.*
AU  - de Bakker, P.I.W.*
AU  - Asselbergs, F.W.*
AU  - Srikanth, V.*
AU  - Thomson, R.J.*
AU  - McWhirter, R.E.*
AU  - Moran, C.*
AU  - Callisaya, M.*
AU  - Phan, T.*
AU  - Rutten-Jacobs, L.C.A.*
AU  - Bevan, S.*
AU  - Tzourio, C.*
AU  - Mather, K.A.*
AU  - Sachdev, P.S.*
AU  - van Duijn, C.M.*
AU  - Worrall, B.B.*
AU  - Dichgans, M.*
AU  - Kittner, S.J.*
AU  - Markus, H.S.*
AU  - Ikram, M.A.*
AU  - Fornage, M.*
AU  - Launer, L.J.*
AU  - Seshadri, S.*
AU  - Longstreth, W.T. Jr.*
AU  - Debette, S.*
AU  - Müller-Nurasyid, M.
AU  - Strauch, K.
AU  - Baumert, J.J.
AU  - Meisinger, C.
AU  - Wichmann, H.-E.
AU  - Illig, T.
AU  - Klopp, N.
AU  - Lichtner, P.
C1  - 65060
C2  - 52026
SP  - e486-e503
TI  - Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting.
JO  - Neurology
VL  - 92
IS  - 5
PY  - 2019
SN  - 0028-3878
ER  - 

TY  - JOUR
AB  - OBJECTIVE: To determine whether serum magnesium and calcium concentrations are causally associated with ischemic stroke or any of its subtypes using the mendelian randomization approach. METHODS: Analyses were conducted using summary statistics data for 13 single-nucleotide polymorphisms robustly associated with serum magnesium (n = 6) or serum calcium (n = 7) concentrations. The corresponding data for ischemic stroke were obtained from the MEGASTROKE consortium (34,217 cases and 404,630 noncases). RESULTS: In standard mendelian randomization analysis, the odds ratios for each 0.1 mmol/L (about 1 SD) increase in genetically predicted serum magnesium concentrations were 0.78 (95% confidence interval [CI] 0.69-0.89; p = 1.3 × 10-4) for all ischemic stroke, 0.63 (95% CI 0.50-0.80; p = 1.6 × 10-4) for cardioembolic stroke, and 0.60 (95% CI 0.44-0.82; p = 0.001) for large artery stroke; there was no association with small vessel stroke (odds ratio 0.90, 95% CI 0.67-1.20; p = 0.46). Only the association with cardioembolic stroke was robust in sensitivity analyses. There was no association of genetically predicted serum calcium concentrations with all ischemic stroke (per 0.5 mg/dL [about 1 SD] increase in serum calcium: odds ratio 1.03, 95% CI 0.88-1.21) or with any subtype. CONCLUSIONS: This study found that genetically higher serum magnesium concentrations are associated with a reduced risk of cardioembolic stroke but found no significant association of genetically higher serum calcium concentrations with any ischemic stroke subtype.
AU  - Larsson, S.C.*
AU  - Traylor, M.*
AU  - Burgess, S.*
AU  - Boncoraglio, G.B.*
AU  - Jern, C.*
AU  - Michaëlsson, K.*
AU  - Markus, H.S.*
AU  - MEGASTROKE Consortium (Müller-Nurasyid, M.
AU  - Strauch, K.)
C1  - 56045
C2  - 46755
SP  - e944-e950
TI  - Serum magnesium and calcium levels in relation to ischemic stroke: Mendelian randomization study.
JO  - Neurology
VL  - 92
IS  - 9
PY  - 2019
SN  - 0028-3878
ER  - 

TY  - JOUR
AB  - ObjectiveTo examine the causal relevance of lifelong differences in low-density lipoprotein cholesterol (LDL-C) for ischemic stroke (IS) relative to that for coronary heart disease (CHD) using a Mendelian randomization approach.MethodsWe undertook a 2-sample Mendelian randomization, based on summary data, to estimate the causal relevance of LDL-C for risk of IS and CHD. Information from 62 independent genetic variants with genome-wide significant effects on LDL-C levels was used to estimate the causal effects of LDL-C for IS and IS subtypes (based on 12,389 IS cases from METASTROKE) and for CHD (based on 60,801 cases from CARDIoGRAMplusC4D). We then assessed the effects of LDL-C on IS and CHD for heterogeneity.ResultsA 1 mmol/L higher genetically determined LDL-C was associated with a 50% higher risk of CHD (odds ratio [OR] 1.49, 95% confidence interval [CI] 1.32-1.68, p = 1.1 x 10(-8)). By contrast, the causal effect of LDL-C was much weaker for IS (OR 1.12, 95% CI 0.96-1.30, p = 0.14; p for heterogeneity = 2.6 x 10(-3)) and, in particular, for cardioembolic stroke (OR 1.06, 95% CI 0.84-1.33, p = 0.64; p for heterogeneity = 8.6 x 10(-3)) when compared with that for CHD.ConclusionsIn contrast with the consistent effects of LDL-C-lowering therapies on IS and CHD, genetic variants that confer lifelong LDL-C differences show a weaker effect on IS than on CHD. The relevance of etiologically distinct IS subtypes may contribute to the differences observed.
AU  - Valdes-Marquez, E.*
AU  - Parish, S.*
AU  - Clarke, R.*
AU  - Stari, T.*
AU  - Worrall, B.B.*
AU  - Hopewell, J.C.*
AU  - METASTROKE Consortium (Lichtner, P.)
C1  - 55933
C2  - 46670
CY  - Two Commerce Sq, 2001 Market St, Philadelphia, Pa 19103 Usa
SP  - E1176-E1187
TI  - Relative effects of LDL-C on ischemic stroke and coronary disease: A Mendelian randomization study.
JO  - Neurology
VL  - 92
IS  - 11
PB  - Lippincott Williams & Wilkins
PY  - 2019
SN  - 0028-3878
ER  - 

TY  - JOUR
AB  - Objective: To determine whether common variants in familial cerebral small vessel disease (SVD) genes confer risk of sporadic cerebral SVD. Methods: We meta-analyzed genotype data from individuals of European ancestry to determine associations of common single nucleotide polymorphisms (SNPs) in 6 familial cerebral SVD genes (COL4A1, COL4A2, NOTCH3, HTRA1, TREX1, and CECR1) with intracerebral hemorrhage (ICH) (deep, lobar, all; 1,878 cases, 2,830 controls) and ischemic stroke (IS) (lacunar, cardioembolic, large vessel disease, all; 19,569 cases, 37,853 controls). We applied data quality filters and set statistical significance thresholds accounting for linkage disequilibrium and multiple testing. Results: A locus in COL4A2 was associated (significance threshold p , 3.5 3 1024) with both lacunar IS (lead SNP rs9515201: odds ratio [OR] 1.17, 95%confidence interval [CI] 1.11-1.24, p 56.62 31028) and deep ICH (lead SNP rs4771674: OR 1.28, 95%CI 1.13-1.44, p 55.76 3 1025). A SNP in HTRA1 was associated (significance threshold p , 5.5 3 1024) with lacunar IS (rs79043147: OR 1.23, 95%CI 1.10-1.37, p 5 1.90 3 1024) and less robustly with deep ICH. There was no clear evidence for association of common variants in either COL4A2 or HTRA1 with non-SVD strokes or in any of the other genes with any stroke phenotype.
AU  - Rannikme, K.*
AU  - Sivakumaran, V.*
AU  - Millar, H.*
AU  - Malik, R.*
AU  - Anderson, C.D.*
AU  - Chong, M.*
AU  - Dave, T.*
AU  - Falcone, G.J.*
AU  - Fernandez-Cadenas, I.*
AU  - Jimenez-Conde, J.*
AU  - Lindgren, A.*
AU  - Montaner, J.*
AU  - O'Donnell, M.*
AU  - Paré, G.*
AU  - Radmanesh, F.*
AU  - Rost, N.S.*
AU  - Slowik, A.*
AU  - Söderholm, M.*
AU  - SIGN study group (Gieger, C.)
AU  - SIGN study group (Meisinger, C.)
AU  - SIGN study group (Müller-Nurasyid, M.)
AU  - SIGN study group (Strauch, K.)
AU  - SIGN study group (Waldenberger, M.)
AU  - METASTROKE Consortium (Liu, J.)
AU  - Mitchell, B.D.*
AU  - Dichgans, M.*
AU  - Rosand, J.*
AU  - Sudlow, C.L.M.*
AU  - SIGN study group (Peters, A.)
C1  - 52324
C2  - 43862
SP  - 1829-1839
TI  - COL4A2 is associated with lacunar ischemic stroke and deep ICH: Meta-analyses among 21,500 cases and 40,600 controls.
JO  - Neurology
VL  - 89
IS  - 17
PY  - 2017
SN  - 0028-3878
ER  - 

TY  - JOUR
AB  - OBJECTIVE: To report atypical MRI patterns associated with POLR3A and POLR3B mutations. METHODS: This was a multicenter retrospective study to collect neuroradiologic, clinical, and molecular data of patients with mutations in POLR3A and POLR3B without the classic MRI phenotype, i.e., diffuse hypomyelination associated with relative T2 hypointensity of the ventrolateral thalamus, globus pallidus, optic radiation, corticospinal tract at the level of the internal capsule, and dentate nucleus, cerebellar atrophy, and thinning of the corpus callosum. RESULTS: Eight patients were identified: 6 carried mutations in POLR3A and 2 in POLR3B. We identified 2 novel MRI patterns: 4 participants presented a selective involvement of the corticospinal tracts, specifically at the level of the posterior limbs of the internal capsules; 4 patients presented moderate to severe cerebellar atrophy. Incomplete hypomyelination was observed in 5 participants. CONCLUSION: Diffuse hypomyelination is not an obligatory feature of POLR3-related disorders. Two distinct patterns, selective involvement of the corticospinal tracts and cerebellar atrophy, are added to the MRI presentation of POLR3-related disorders.
AU  - la Piana, R.*
AU  - Cayami, F.K.*
AU  - Tran, L.T.*
AU  - Guerrero, K.*
AU  - van Spaendonk, R.*
AU  - Ounap, K.*
AU  - Pajusalu, S.*
AU  - Haack, T.B.
AU  - Wassmer, E.*
AU  - Timmann, D.*
AU  - Mierzewska, H.*
AU  - Poll-The, B.T.*
AU  - Patel, C.*
AU  - Cox, H.*
AU  - Atik, T.*
AU  - Onay, H.*
AU  - Ozkınay, F.*
AU  - Vanderver, A.*
AU  - van der Knaap, M.S.*
AU  - Wolf, N.I.*
AU  - Bernard, G.*
C1  - 48229
C2  - 41015
CY  - Philadelphia
SP  - 1622-1626
TI  - Diffuse hypomyelination is not obligate for POLR3-related disorders.
JO  - Neurology
VL  - 86
IS  - 17
PB  - Lippincott Williams & Wilkins
PY  - 2016
SN  - 0028-3878
ER  - 

TY  - JOUR
AB  - OBJECTIVE: To investigate the influence of common and low-frequency genetic variants on the risk of ischemic stroke (all IS) and etiologic stroke subtypes. METHODS: We meta-analyzed 12 individual genome-wide association studies comprising 10,307 cases and 19,326 controls imputed to the 1000 Genomes (1 KG) phase I reference panel. We selected variants showing the highest degree of association (p < 1E-5) in the discovery phase for replication in Caucasian (13,435 cases and 29,269 controls) and South Asian (2,385 cases and 5,193 controls) samples followed by a transethnic meta-analysis. We further investigated the p value distribution for different bins of allele frequencies for all IS and stroke subtypes. RESULTS: We showed genome-wide significance for 4 loci: ABO for all IS, HDAC9 for large vessel disease (LVD), and both PITX2 and ZFHX3 for cardioembolic stroke (CE). We further refined the association peaks for ABO and PITX2. Analyzing different allele frequency bins, we showed significant enrichment in low-frequency variants (allele frequency <5%) for both LVD and small vessel disease, and an enrichment of higher frequency variants (allele frequency 10% and 30%) for CE (all p < 1E-5). CONCLUSIONS: Our findings suggest that the missing heritability in IS subtypes can in part be attributed to low-frequency and rare variants. Larger sample sizes are needed to identify the variants associated with all IS and stroke subtypes.
AU  - Malik, R.*
AU  - Traylor, M.*
AU  - Pulit, S.L.*
AU  - Bevan, S.*
AU  - Hopewell, J.C.*
AU  - Holliday, E.G.*
AU  - Zhao, W.*
AU  - Abrantes, P.*
AU  - Amouyel, P.*
AU  - Attia, J.R.*
AU  - Battey, T.W.*
AU  - Berger, K.*
AU  - Boncoraglio, G.B.*
AU  - Chauhan, G.*
AU  - Cheng, Y.C.*
AU  - Chen, W.M.*
AU  - Clarke, R.*
AU  - Cotlarciuc, I.*
AU  - Debette, S.*
AU  - Falcone, G.J.*
AU  - Ferro, J.M.*
AU  - Gamble, D.M.*
AU  - Ilinca, A.*
AU  - Kittner, S.J.*
AU  - Kourkoulis, C.E.*
AU  - Lemmens, R.*
AU  - Levi, C.R.*
AU  - Lichtner, P.
AU  - Lindgren, A.*
AU  - Liu, J.*
AU  - Meschia, J.F.*
AU  - Mitchell, B.D.*
AU  - Oliveira, S.A.*
AU  - Pera, J.*
AU  - Reiner, A.P.*
AU  - Rothwell, P.M.*
AU  - Sharma, P.*
AU  - Slowik, A.*
AU  - Sudlow, C.L.*
AU  - Tatlisumak, T.*
AU  - Thijs, V.*
AU  - Vicente, A.M.*
AU  - Woo, D.*
AU  - Seshadri, S*
AU  - Saleheen, D.*
AU  - Rosand, J.*
AU  - Markus, H.S.*
AU  - Worrall, B.B.*
AU  - Dichgans, M.*
C1  - 48045
C2  - 40832
CY  - Philadelphia
SP  - 1217-1226
TI  - Low-frequency and common genetic variation in ischemic stroke: The METASTROKE collaboration.
JO  - Neurology
VL  - 86
IS  - 13
PB  - Lippincott Williams & Wilkins
PY  - 2016
SN  - 0028-3878
ER  - 

TY  - JOUR
AB  - Recent publications on both the genetics and environmental factors of restless legs syndrome (RLS) defined as a clinical disorder suggest that overlapping genetic risk factors may play a role in primary (idiopathic) and secondary (symptomatic) RLS. Following a systematic literature search of RLS associated with comorbidities, we identified an increased prevalence of RLS only in iron deficiency and kidney disease. In cardiovascular disease, arterial hypertension, diabetes, migraine, and Parkinson disease, the methodology of studies was poor, but an association might be possible. There is insufficient evidence for conditions such as anemia (without iron deficiency), chronic obstructive pulmonary disease, multiple sclerosis, headache, stroke, narcolepsy, and ataxias. Based on possible gene-microenvironmental interaction, the classifications primary and secondary RLS may suggest an inappropriate causal relation. We recognize that in some conditions, treatment of the underlying disease should be achieved as far as possible to reduce or eliminate RLS symptoms. RLS might be seen as a continuous spectrum with a major genetic contribution at one end and a major environmental or comorbid disease contribution at the other.
AU  - Trenkwalder, C.*
AU  - Allen, R.P.*
AU  - Högl, B.*
AU  - Paulus, W.*
AU  - Winkelmann, J.
C1  - 48042
C2  - 39865
CY  - Philadelphia
SP  - 1336-1343
TI  - Restless legs syndrome associated with major diseases: A systematic review and new concept.
JO  - Neurology
VL  - 86
IS  - 14
PB  - Lippincott Williams & Wilkins
PY  - 2016
SN  - 0028-3878
ER  - 

TY  - JOUR
AB  - Objectives: We aim to clarify the pathogenic role of intermediate size repeat expansions of SCA2, SCA3, SCA6, and SCA17 as risk factors for idiopathic Parkinson disease (PD). Methods: We invited researchers from the Genetic Epidemiology of Parkinson's Disease Consortium to participate in the study. There were 12,346 cases and 8,164 controls genotyped, for a total of 4 repeats within the SCA2, SCA3, SCA6, and SCA17 genes. Fixed- and random-effects models were used to estimate the summary risk estimates for the genes. We investigated between-study heterogeneity and heterogeneity between different ethnic populations. Results: We did not observe any definite pathogenic repeat expansions for SCA2, SCA3, SCA6, and SCA17 genes in patients with idiopathic PD from Caucasian and Asian populations. Furthermore, overall analysis did not reveal any significant association between intermediate repeats and PD. The effect estimates (odds ratio) ranged from 0.93 to 1.01 in the overall cohort for the SCA2, SCA3, SCA6, and SCA17 loci. Conclusions: Our study did not support a major role for definite pathogenic repeat expansions in SCA2, SCA3, SCA6, and SCA17 genes for idiopathic PD. Thus, results of this large study do not support diagnostic screening of SCA2, SCA3, SCA6, and SCA17 gene repeats in the common idiopathic form of PD. Likewise, this largest multicentered study performed to date excludes the role of intermediate repeats of these genes as a risk factor for PD.
AU  - Wang, L.*
AU  - Aasly, J.O.*
AU  - Annesi, G.*
AU  - Bardien, S.*
AU  - Bozi, M.*
AU  - Brice, A.*
AU  - Carr, J.J.*
AU  - Chung, S.J.*
AU  - Clarke, C.*
AU  - Crosiers, D.*
AU  - Deutschländer, A.*
AU  - Eckstein, G.N.
AU  - Farrer, M.J.*
AU  - Goldwurm, S.*
AU  - Garraux, G.*
AU  - Hadjigeorgiou, G.M.*
AU  - Hicks, A.A.*
AU  - Hattori, N.*
AU  - Klein, C.*
AU  - Jeon, B.*
AU  - Kim, Y.J.*
AU  - Lesage, S.*
AU  - Lin, J.J.*
AU  - Lynch, T.*
AU  - Lichtner, P.
AU  - Lang, A.E.*
AU  - Mok, V.*
AU  - Jasinska-Myga, B.*
AU  - Mellick, G.D.*
AU  - Morrison, K.E.*
AU  - Opala, G.*
AU  - Pihlstrom, L.*
AU  - Pramstaller, P.P.*
AU  - Park, S.S.*
AU  - Quattrone, A.*
AU  - Rogaeva, E.*
AU  - Ross, O.A.*
AU  - Stefanis, L.*
AU  - Stockton, J.D.*
AU  - Silburn, P.A.*
AU  - Theuns, J.*
AU  - Tan, E.K.*
AU  - Tomiyama, H.*
AU  - Toft, M.F.*
AU  - van Broeckhoven, C.*
AU  - Uitti, R.J.*
AU  - Wirdefeldt, K.*
AU  - Wszolek, Z.*
AU  - Xiromerisiou, G.*
AU  - Yueh, K.C.*
AU  - Zhao, Y.*
AU  - Gasser, T.*
AU  - Maraganore, D.M.*
AU  - Kruger, R.*
AU  - Sharma, M.*
C1  - 47131
C2  - 39203
SP  - 1283-1292
TI  - Large-scale assessment of polyglutamine repeat expansions in Parkinson disease.
JO  - Neurology
VL  - 85
IS  - 15
PY  - 2015
SN  - 0028-3878
ER  - 

TY  - JOUR
AB  - OBJECTIVES: The study was focused on leukoencephalopathies of unknown cause in order to define a novel, homogeneous phenotype suggestive of a common genetic defect, based on clinical and MRI findings, and to identify the causal genetic defect shared by patients with this phenotype. METHODS: Independent next-generation exome-sequencing studies were performed in 2 unrelated patients with a leukoencephalopathy. MRI findings in these patients were compared with available MRIs in a database of unclassified leukoencephalopathies; 11 patients with similar MRI abnormalities were selected. Clinical and MRI findings were investigated. RESULTS: Next-generation sequencing revealed compound heterozygous mutations in AARS2 encoding mitochondrial alanyl-tRNA synthetase in both patients. Functional studies in yeast confirmed the pathogenicity of the mutations in one patient. Sanger sequencing revealed AARS2 mutations in 4 of the 11 selected patients. The 6 patients with AARS2 mutations had childhood- to adulthood-onset signs of neurologic deterioration consisting of ataxia, spasticity, and cognitive decline with features of frontal lobe dysfunction. MRIs showed a leukoencephalopathy with striking involvement of left-right connections, descending tracts, and cerebellar atrophy. All female patients had ovarian failure. None of the patients had signs of a cardiomyopathy. CONCLUSIONS: Mutations in AARS2 have been found in a severe form of infantile cardiomyopathy in 2 families. We present 6 patients with a new phenotype caused by AARS2 mutations, characterized by leukoencephalopathy and, in female patients, ovarian failure, indicating that the phenotypic spectrum associated with AARS2 variants is much wider than previously reported.
AU  - Dallabona, C.*
AU  - Diodato, D.*
AU  - Kevelam, S.H.*
AU  - Haack, T.B.
AU  - Wong, L.J.*
AU  - Salomons, G.S.*
AU  - Baruffini, E.*
AU  - Melchionda, L.*
AU  - Mariotti, C.*
AU  - Strom, T.M.
AU  - Meitinger, T.
AU  - Prokisch, H.
AU  - Chapman, K.*
AU  - Colley, A.*
AU  - Rocha, H.*
AU  - Ounap, K.*
AU  - Schiffmann, R.*
AU  - Salsano, E.*
AU  - Savoiardo, M.*
AU  - Hamilton, E.M.*
AU  - Abbink, T.E.M.*
AU  - Wolf, N.I.*
AU  - Ferrero, I.*
AU  - Lamperti, C.*
AU  - Zeviani, M.*
AU  - Vanderver, A.*
AU  - Ghezzi, D.*
AU  - van der Knaap, M.S.*
C1  - 31248
C2  - 34251
CY  - Philadelphia
SP  - 2063-2071
TI  - Novel (ovario) leukodystrophy related to AARS2 mutations.
JO  - Neurology
VL  - 82
IS  - 23
PB  - Lippincott Williams & Wilkins
PY  - 2014
SN  - 0028-3878
ER  - 

TY  - JOUR
AB  - OBJECTIVES: To determine the nature and frequency of HSJ1 mutations in patients with hereditary motor and hereditary motor and sensory neuropathies. METHODS: Patients were screened for mutations by genome-wide or targeted linkage and homozygosity studies, whole-exome sequencing, and Sanger sequencing. RNA and protein studies of skin fibroblasts were used for functional characterization. RESULTS: We describe 2 additional mutations in the HSJ1 gene in a cohort of 90 patients with autosomal recessive distal hereditary motor neuropathy (dHMN) and Charcot-Marie-Tooth disease type 2 (CMT2). One family with a dHMN phenotype showed the homozygous splice-site mutation c.229+1G>A, which leads to retention of intron 4 in the HSJ1 messenger RNA with a premature stop codon and loss of protein expression. Another family, presenting with a CMT2 phenotype, carried the homozygous missense mutation c.14A>G (p.Tyr5Cys). This mutation was classified as likely disease-related by several automatic algorithms for prediction of possible impact of an amino acid substitution on the structure and function of proteins. Both mutations cosegregated with autosomal recessive inheritance of the disease and were absent from the general population. CONCLUSIONS: Taken together, in our cohort of 90 probands, we confirm that HSJ1 mutations are a rare but detectable cause of autosomal recessive dHMN and CMT2. We provide clinical and functional information on an HSJ1 splice-site mutation and report the detailed phenotype of 2 patients with CMT2, broadening the phenotypic spectrum of HSJ1-related neuropathies.
AU  - Gess, B.*
AU  - Auer-Grumbach, M.*
AU  - Schirmacher, A.*
AU  - Strom, T.M.
AU  - Zitzelsberger, M.*
AU  - Rudnik-Schöneborn, S.*
AU  - Röhr, D.*
AU  - Halfter, H.*
AU  - Young, P.*
AU  - Senderek, J.*
C1  - 32431
C2  - 35087
SP  - 1726-1732
TI  - HSJ1-related hereditary neuropathies: Novel mutations and extended clinical spectrum.
JO  - Neurology
VL  - 83
IS  - 19
PY  - 2014
SN  - 0028-3878
ER  - 

TY  - JOUR
AU  - Schirmer, L.*
AU  - Srivastava, R.*
AU  - Kalluri, S.R.*
AU  - Boettinger, S.*
AU  - Carassiti, D.*
AU  - Srivastava, B.
AU  - Schlegel, J.*
AU  - Kuhlmann, T.*
AU  - Korn, T.*
AU  - Reynolds, R.*
AU  - Hemmer, B.*
C1  - 47031
C2  - 40482
TI  - Differential Loss of KIR4.1 on Oligodendrocytes and Astrocytes in Multiple Sclerosis Lesions.
JO  - Neurology
VL  - 80
PY  - 2013
SN  - 0028-3878
ER  - 

TY  - JOUR
AB  - 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. Copyright © 2012 by AAN Enterprises, Inc.
AU  - Sharma, M.L.*
AU  - Ioannidis, J.P.A.*
AU  - Aasly, J.O.*
AU  - Annesi, G.*
AU  - Brice, A.*
AU  - van Broeckhoven, C.L.*
AU  - Bertram, L.*
AU  - Bozi, M.*
AU  - Crosiers, D.*
AU  - Clarke, C.E.*
AU  - Facheris, M.F.*
AU  - Farrer, M.J.*
AU  - Garraux, G.*
AU  - Gispert, S.*
AU  - Auburger, G.W.J.*
AU  - Vilariño-Güell, C.*
AU  - Hadjigeorgiou, G.M.*
AU  - Hicks, A.A.*
AU  - Hattori, N.*
AU  - Jeon, B.*
AU  - Lesage, S.R.*
AU  - Lill, C.M.*
AU  - Lin, J.*
AU  - Lynch, T.M.*
AU  - Lichtner, P.K.
AU  - Lang, A.*
AU  - Mok, V.*
AU  - Jasinska-Myga, B.*
AU  - Mellick, G.D.*
AU  - Morrison, K.E.*
AU  - Opala, G.M.*
AU  - Pramstaller, P.P.*
AU  - Pichler, I.*
AU  - Park, S.H.*
AU  - Quattrone, A.*
AU  - Rogaeva, E.A.*
AU  - Ross, O.A.*
AU  - Stefanis, L.*
AU  - Stockton, J.D.*
AU  - Satake, W.*
AU  - Silburn, P.A.S.*
AU  - Theuns, J.*
AU  - Tan, E.K.*
AU  - Toda, T.*
AU  - Tomiyama, H.*
AU  - Uitti, R.J.*
AU  - Wirdefeldt, K.*
AU  - Wszołek, Z.K.*
AU  - Xiromerisiou, G.*
AU  - Yueh, K.C.*
AU  - Zhao, Y.*
AU  - Gasser, T.H.*
AU  - Maraganore, D.M.*
AU  - Kruger, R.*
C1  - 32951
C2  - 30189
SP  - 659-667
TI  - Large-scale replication and heterogeneity in Parkinson disease genetic loci.
JO  - Neurology
VL  - 79
IS  - 7
PY  - 2012
SN  - 0028-3878
ER  - 

TY  - JOUR
AB  - no Abstract
AU  - Ishikawa, K.*
AU  - Dürr, A.*
AU  - Klopstock, T.*
AU  - Müller, S.*
AU  - de Toffol, B.*
AU  - Vidailhet, M.*
AU  - Vighetto, A.*
AU  - Marelli, C.*
AU  - Wichmann, H.-E.
AU  - Illig, T.
AU  - Niimi, Y.*
AU  - Sato, N.*
AU  - Amino, T.*
AU  - Stevanin, G.*
AU  - Brice, A.*
AU  - Mizusawa, H.*
C1  - 3968
C2  - 29399
SP  - 1853-1855
TI  - Pentanucleotide repeats at the spinocerebellar ataxia type 31 (SCA31) locus in Caucasians.
JO  - Neurology
VL  - 77
IS  - 20
PB  - Lippincott Williams&Wilkins
PY  - 2011
SN  - 0028-3878
ER  - 

TY  - JOUR
AU  - Schulte, E.C.*
AU  - Knauf, F.
AU  - Kemlink, D.*
AU  - Schormair, B.
AU  - Lichtner, P.
AU  - Gieger, C.
AU  - Meitinger, T.
AU  - Winkelmann, J.
C1  - 6243
C2  - 28865
CY  - Philadelphia, MA
SP  - 1106-1108
TI  - Variant screening of the coding regions of MEIS1 in patients with restless legs syndrome.
JO  - Neurology
VL  - 76
IS  - 12
PB  - Lippincott Williams & Wilkins
PY  - 2011
SN  - 0028-3878
ER  - 

TY  - JOUR
AB  - Objective: Our aim was to investigate whether the risk of febrile seizures is influenced by a common functional polymorphism in the sodium channel gene SCN1A. This single nucleotide polymorphism (IVS5N + 5 G > A, rs3812718) was shown to modify the proportion of two alternative transcripts of the channel. Methods: We performed an exploratory case-control association analysis in 90 adult epilepsy patients with childhood febrile seizures vs 486 epilepsy patients without a history of febrile seizures and also vs 701 population controls. In the replication step, we investigated children with febrile seizures without concomitant epilepsy at the time of their inclusion. We compared the genotypes of 55 of those children against population controls and performed a within-family association analysis in an additional 88 child-parent trios with febrile seizures. Results: We observed a significant association of the splice-site interrupting A-allele with febrile seizures (p value in the exploratory step: 0.000017; joint p value of the replication: 0.00069). Our data suggest that the A-allele of this variant confers a threefold genotype relative risk in homozygotes and accounts for a population attributable fraction of up to 50% for the etiology of febrile seizures. Conclusions: The A-allele of the SCN1A single nucleotide polymorphism IVS5N + 5 G > A (rs3812718) represents a common and relevant risk factor for febrile seizures. A limitation of the present study is that patients of the exploratory and replication steps differed in aspects of their phenotype (febrile seizures with and without additional epilepsy).
AU  - Schlachter, K.*
AU  - Gruber-Sedlmayr, U.*
AU  - Stogmann, E.*
AU  - Lausecker, M.*
AU  - Hotzy, C.*
AU  - Balzar, J.*
AU  - Schuh, E.*
AU  - Baumgartner, C.*
AU  - Mueller, J.C.*
AU  - Illig, T.
AU  - Wichmann, H.-E.
AU  - Lichtner, P.
AU  - Meitinger, T.
AU  - Strom, T.M.
AU  - *
AU  - Zimprich, F.*
C1  - 2057
C2  - 26407
SP  - 974-978
TI  - A splice site variant in the sodium channel gene SCN1A confers risk of febrile seizures.
JO  - Neurology
VL  - 72
IS  - 11
PB  - Lippincott Williams & Wilkins
PY  - 2009
SN  - 0028-3878
ER  - 

TY  - JOUR
AU  - Winkelmann, J.
AU  - Müller-Myhsok, B.*
C1  - 5033
C2  - 26352
CY  - PHILADELPHIA, PA
SP  - 664-665
TI  - Genetics of restless legs syndrome - A burning urge to move.
JO  - Neurology
VL  - 70
IS  - 9
PB  - LIPPINCOTT WILLIAMS & WILKINS
PY  - 2008
SN  - 0028-3878
ER  - 

TY  - JOUR
AU  - Fernández-Santiago, R.*
AU  - Sharma, M.*
AU  - Mueller, J.C.*
AU  - Gohlke, H.
AU  - Illig, T.
AU  - Anneser, J.*
AU  - Münch, C.*
AU  - Ludolph, A.*
AU  - Kamm, C.*
AU  - Gasser, T.*
C1  - 5796
C2  - 24252
SP  - 1929-1931
TI  - Possible gender-dependent association of vascular endothelial growth factor (VEGF) gene and ALS.
JO  - Neurology
VL  - 66
PY  - 2006
SN  - 0028-3878
ER  - 

TY  - JOUR
AU  - Kamm, C.*
AU  - Asmus, F.*
AU  - Müller, J.*
AU  - Mayer, P.*
AU  - Sharma, M.*
AU  - Muller, U.J.*
AU  - Beckert, S.*
AU  - Ehling, R.*
AU  - Illig, T.
AU  - Wichmann, H.-E.
AU  - Poewe, W.*
AU  - Mueller, J.C.*
AU  - Gasser, T.*
C1  - 3121
C2  - 24250
SP  - 1857-1859
TI  - Strong genetic evidence for association of TOR1A/TOR1B with idiopathic dystonia.
JO  - Neurology
VL  - 67
PY  - 2006
SN  - 0028-3878
ER  - 

TY  - JOUR
AU  - Liebetanz, K.M.*
AU  - Winkelmann, J.
AU  - Trenkwalder, C.*
AU  - Pütz, B.*
AU  - Dichgans, M.*
AU  - Gasser, T.*
AU  - Müller-Myhsok, B.*
C1  - 636
C2  - 24179
SP  - 320-321
TI  - RLS3: Fine-mapping of an autosomal dominant locus in a family with intrafamilial heterogeneity.
JO  - Neurology
VL  - 67
PY  - 2006
SN  - 0028-3878
ER  - 

TY  - JOUR
AU  - Schulte, C.*
AU  - Sharma, M.*
AU  - Müller, J.C.*
AU  - Lichtner, P.
AU  - Prestel, J.*
AU  - Berg, D.*
AU  - Gasser, T.*
C1  - 5106
C2  - 24214
SP  - 2080-2082
TI  - Comprehensive association analysis of the NOS2A gene with Parkinson disease.
JO  - Neurology
VL  - 67
PY  - 2006
SN  - 0028-3878
ER  - 

TY  - JOUR
AB  - We sequenced 61 patients with various idiopathic generalized epilepsy (IGE) syndromes for mutations in the EFHC1 gene. We detected three novel heterozygous missense mutations (I174V, C259Y, A394S) and one possibly pathogenic variant in the 3' UTR (2014t>c). The mutation I174V was also detected in 1 of 372 screened patients with temporal lobe epilepsy. We conclude that mutations in the EFHC1 gene may underlie different types of epilepsy syndromes.
AU  - Stogmann, E.*
AU  - Lichtner, P.
AU  - Baumgartner, C.*
AU  - Bonelli, S.*
AU  - Assem-Hilger, E.*
AU  - Leutmezer, F.*
AU  - Schmied, M.*
AU  - Hotzy, C.*
AU  - Strom, T.M.
AU  - Meitinger, T.
AU  - Zimprich, F.*
AU  - *
C1  - 2265
C2  - 24215
SP  - 2029-2031
TI  - Idiopathic generalized epilepsy phenotypes associated with different EFHC1 mutations.
JO  - Neurology
VL  - 67
IS  - 11
PY  - 2006
SN  - 0028-3878
ER  - 

TY  - JOUR
AU  - Hörtnagel, K.
AU  - Nardocci, N.*
AU  - Zorzi, G.*
AU  - Garavaglia, B.*
AU  - Botz, E.
AU  - Meitinger, T.
AU  - Klopstock, T.*
C1  - 5295
C2  - 22505
SP  - 922-924
TI  - Infantile neuroaxonal dystrophy and pantothenate kinase-associated neurodegeneration: Locus heterogeneity.
JO  - Neurology
VL  - 63
PY  - 2004
SN  - 0028-3878
ER  - 

TY  - JOUR
AU  - Riemenschneider, M.*
AU  - Klopp, N.
AU  - Xiang, W.*
AU  - Wagenpfeil, S.*
AU  - Vollmert, C.
AU  - Müller, U.*
AU  - Förstl, H.*
AU  - Illig, T.
AU  - Kretschmar, H.*
AU  - Kurz, A.*
C1  - 1357
C2  - 22271
SP  - 364-366
TI  - Prion protein codon 129 polymorphism and risk of Alzheimer disease.
JO  - Neurology
VL  - 63
PY  - 2004
SN  - 0028-3878
ER  -