Soto‐Beasley, Alexandra I.

Abstract Objective To determine whether distinct microtubule‐associated protein tau MAPT H1 subhaplotypes are associated with clinical and demographic features in Parkinson’s disease. Methods A retrospective cohort study included 855 unrelated Caucasian patients with Parkinson’s disease who were seen by Movement Disorder specialists at the Mayo Clinic Florida between 1998 and 2016. The primary outcome measures were specific demographic and clinical features of Parkinson’s disease, including age at onset, disease progression, survival, motor signs, dementia, dystonia, dyskinesia, autonomic dysfunction, impulse control disorder, psychiatric features, REM sleep behavior disorder, restless legs syndrome, and Parkinson’s disease subtype. Specific clinical features were measured at the initial visit and most recent visit. These outcomes were assessed for association with MAPT H1 subhaplotypes, which were defined by six haplotype tagging variants. Results Median onset age was 64 years (range: 22‐94 years); 548 (64%) of patients were male. Significant associations ( P < 0.0029) were observed between MAPT H1b and orthostatic hypotension (OR = 1.72, P = 0.001); between H1j and rest tremor (OR = 0.15; P < 0.001) as well as REM sleep behavior disorder (OR = 3.87, P < 0.001); between H1r and bradykinesia (OR = 0.11; P < 0.001); and between H1v and restless legs syndrome (OR = 4.02, P = 0.002). Interpretation Four MAPT H1 subhaplotypes, but not the H2 haplotype, were significantly associated with specific clinical features in Parkinson’s disease. MAPT haplotypic structure may explain some of the phenotypic variability in disease. Replication of our findings will be critical to fully resolve the Parkinson’s disease risk association signal at Chr17q21.

Abstract A number of efforts are underway to better understand the role of genetic variation in successful aging and longevity. However, to date, only two genes have been consistently associated with longevity in humans: APOE and FOXO3, with the APOE ɛ2 allele also protective against dementia. Recently, using an exome-wide SNP array approach, a missense variant CLEC3B c.316G&gt;A (rs13963 p.S106G) was reported to associate with longevity in two independent cohorts of Japanese and Chinese participants. Interestingly, CLEC3B p.S106G is more frequent in Caucasian populations. Herein, we examined the frequency of CLEC3B p.S106G in a Caucasian series of 1,483 neurologically healthy individuals with a specific subset &gt;80 years of age. Although our findings do not support an association between CLEC3B p.S106G and aging without neurological disease (p = .89), we confirmed the association between the APOE ε2 allele and better survival without neurological disease (p = .001). Further assessment of healthy aged cohorts that retain intact neurological function will be critical to understand the etiology of neurodegenerative disease and the role of age at risk.

ABSTRACTBackgroundMutations in the leucine‐rich repeat kinase 2 gene (LRRK2) are the most common genetic cause of Parkinson's disease (PD). Unexpectedly, tau pathology has been reported in a subset of LRRK2 mutation carriers.MethodsTo estimate the frequency of pathogenic LRRK2 mutations and to evaluate the association of common LRRK2 variants with risk of primary tauopathies, we studied 1039 progressive supranuclear palsy (PSP) and 145 corticobasal degeneration patients from the Mayo Clinic Florida brain bank and 1790 controls ascertained at Mayo Clinic. Sanger sequencing of LRRK2 exons 30, 31, 35, and 41 was performed in all patients, and genotyping of all 17 known exonic variants with minor allele frequency >0.5% was performed in patients and controls.ResultsLRRK2 mutational screening identified 2 known pathogenic mutations (p.G2019S and p.R1441C), each in 1 PSP patient, the novel p.A1413T mutation in a PSP patient and the rare p.R1707K mutation in a corticobasal degeneration patient. Both p.A1413T and p.R1707K mutations were predicted damaging by at least 2 of 3 prediction programs and affect evolutionary conserved sites of LRRK2. Association analysis using common LRRK2 variants only showed nominal association of the p.L153L variant with PSP.ConclusionsOur study confirms the presence of pathogenic and potentially pathogenic LRRK2 mutations in pathologically confirmed primary tauopathies, albeit with low frequency. In contrast to PD, common LRRK2 variants do not appear to play a major role in determining PSP and corticobasal degeneration risk. © 2016 International Parkinson and Movement Disorder Society.

Abstract Introduction The MAPT H1 haplotype has been associated with several neurodegenerative diseases. We were interested in exploring the role of MAPT haplotypic variation in risk of dementia with Lewy bodies (DLB). Method We genotyped six MAPT haplotype tagging SNPs and screened 431 clinical DLB cases, 347 pathologically defined high‐likelihood DLB cases, and 1049 controls. Result We performed haplotypic association tests and detected an association with the protective H2 haplotype in our combined series (odds ratio [OR] = 0.75). We fine‐mapped the locus and identified a relatively rare haplotype, H1G, that is associated with an increased risk of DLB (OR = 3.30, P = .0017). This association was replicated in our pathologically defined series (OR = 2.26, P = .035). Discussion These results support a role for H1 and specifically H1G in susceptibility to DLB. However, the exact functional variant at the locus is still unknown, and additional studies are warranted to fully explain genetic risk of DLB at the MAPT locus.

BackgroundRecently, a novel mutation in exon 24 of DNAJC13 gene (p.Asn855Ser, rs387907571) has been reported to cause autosomal dominant Parkinson's disease (PD) in a multi‐incident Mennonite family.MethodsIn the present study the mutation containing exon of the DNAJC13 gene has been sequenced in a Caucasian series consisting of 1938 patients with clinical PD and 838 with pathologically diagnosed Lewy body disease (LBD).ResultsOur sequence analysis did not identify any coding variants in exon 24 of DNAJC13. Two previously described variants in intron 23 (rs200204728 and rs2369796) were observed.ConclusionOur results indicate that the region surrounding the DNAJC13 p.Asn855Ser substitution is highly conserved and mutations in this exon are not a common cause of PD or LBD among Caucasian populations.

Background and purposeLow density lipoprotein receptor related proteins (LRPs) 1 and 6 have been implicated in cerebral ischaemia. In addition, genetic variation in LRP1 and LRP6 has been linked with various factors that are related to risk of ischaemic stroke. The aim of this study was to examine the association of LRP1 and LRP6 gene variants with risk of ischaemic stroke as part of the Ischemic Stroke Genetics Study (ISGS).MethodsA Caucasian series (434 stroke patients, 319 controls) and an African American series (161 stroke patients, 116 controls) were included. Fourteen LRP6 variants and three LRP1 variants were genotyped and assessed for association with ischaemic stroke.ResultsIn the Caucasian series, significant associations with ischaemic stroke were observed for LRP6 rs2075241 [odds ratio (OR) 0.42, P = 0.023], rs2302685 (OR 0.44, P = 0.049), rs7975614 (OR 0.07, P = 0.017), rs10492120 (OR 0.62, P = 0.036) and rs10743980 (OR 0.66, P = 0.037). Risk of ischaemic stroke was significantly lower for carriers of any of these five protective LRP6 variants (24.0% of subjects) compared to non‐carriers (OR 0.57, P = 0.003). The protective association for LRP6 rs2075241 was observed at a similar magnitude across ischaemic stroke subtypes, whilst the effects of rs23022685, rs10492120 and rs10743980 were most apparent for cardioembolic and large vessel stroke. In the African American series, LRP1 rs11172113 was associated with an increased risk of stroke (OR 1.89, P = 0.006).ConclusionsThe results of our preliminary study provide evidence that LRP6 and LRP1 variants may be associated with risk of ischaemic stroke. Validation in larger studies is warranted.