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Background Leucoencephalopathy with brain stem and spinal cord involvement and high brain lactate (LBSL) was first defined by characteristic magnetic resonance imaging and spectroscopic findings. The clinical features include childhood or juvenile onset slowly progressive ataxia, spasticity, and dorsal column dysfunction, occasionally accompanied by learning difficulties. Mutations in DARS2 , encoding mitochondrial aspartyl-tRNA synthetase, were recently shown to cause LBSL. The signs and symptoms show some overlap with the most common leucoencephalopathy of young adults, multiple sclerosis (MS). Objective To clarify the molecular background of LBSL patients in Finland, and to look for DARS2 mutations in a group of MS patients. Methods Clinical evaluation of LBSL patients, DARS2 sequencing and haplotype analysis, and carrier frequency determination in Finland. Results All eight LBSL patients were compound heterozygotes for DARS2 mutations: all carried R76SfsX5 change, seven had M134\_K165del, and one had C152F change. Axonal neuropathy was found in five of the eight patients. The carrier frequencies of the R76SfsX5 and M134\_K165del mutations were 1:95 and 1:380, respectively. All patients shared common European haplotypes, suggestive of common European LBSL ancestors. No enrichment of the two common DARS2 mutations was found in 321 MS patients. Conclusion All LBSL patients were compound heterozygotes, which suggests that DARS2 mutation homozygosity may be lethal or manifest as a different phenotype. The authors show here that despite identical mutations the clinical picture was quite variable in the patients. Axonal neuropathy was an important feature of LBSL. DARS2 mutations cause childhood-to-adolescence onset leucoencephalopathy, but they do not seem to be associated with MS.

To clarify the association between anticholinergic drugs and apolipoprotein E epsilon4 allele carrier status (APOE4) and cognitive dysfunction.Cross-sectional analyses of current drug use and cognitive functioning according to the baseline assessments of the Drugs and Evidence-Based Medicine in the Elderly Study.Helsinki, Finland.Four hundred community-dwelling people aged 75 to 90 without clinical dementia but with a history of stable atherosclerotic disease.Cognitive function according to the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating Scale (CDR). Participants' use of anticholinergic drugs was estimated using definitions from previous scientific literature. APOE alleles determined from peripheral blood leukocyte deoxyribonucleic acid using standard polymerase chain reaction-based methods.There was an association between anticholinergic drugs and lower MMSE scores (P for trend.001). The higher the number of anticholinergic drugs, the lower the MMSE score. Subjects with the APOE4 allele and using drugs with anticholinergic properties had the lowest median MMSE score (26), whereas those without the APOE4 allele and not using drugs with anticholinergic properties had the highest median MMSE score (28). When adjusted for age, sex, and education, the difference between the groups remained significant. The finding was similar for CDR scores.Use of drugs with anticholinergic properties was associated with lower cognitive function irrespective of APOE4 carrier status. Having lower cognitive function as a group, APOE4 carriers may be more vulnerable to this undesirable effect, but a follow-up study is needed to demonstrate this.

Large case–control genome-wide association studies primarily expose common variants contributing to disease pathogenesis with modest effects. Thus, alternative strategies are needed to tackle rare, possibly more penetrant alleles. One strategy is to use special populations with a founder effect and isolation, resulting in allelic enrichment. For multiple sclerosis such a unique setting is reported in Southern Ostrobothnia in Finland, where the prevalence and familial occurrence of multiple sclerosis (MS) are exceptionally high. Here, we have studied one of the best replicated MS loci, 5p, and monitored for haplotypes shared among 72 regional MS cases, the majority of which are genealogically distantly related. The haplotype analysis over the 45 Mb region, covering the linkage peak identified in Finnish MS families, revealed only modest association at IL7R (P = 0.04), recently implicated in MS, whereas most significant association was found with one haplotype covering the C7-FLJ40243 locus (P = 0.0001), 5.1 Mb centromeric of IL7R. The finding was validated in an independent sample from the isolate and resulted in an odds ratio of 2.73 (P = 0.000003) in the combined data set. The identified relatively rare risk haplotype contains C7 (complement component 7), an important player of the innate immune system. Suggestive association with alleles of the region was seen also in more heterogeneous populations. Interestingly, also the complement activity correlated with the identified risk haplotype. These results suggest that the MS predisposing locus on 5p is more complex than assumed and exemplify power of population isolates in the identification of rare disease alleles.

Loss-of-function mutations of DAP12 and TREM2 cause a recessively inherited disease PLOSL, manifesting in brain white matter. The genes of the DAP12-TREM2 signaling receptor are located on 19q13.12 and 6p21.1, to which linkage has been observed also in families affected by another immune-mediated demyelinating disease, MS. We have tested if allelic variation in DAP12 or TREM2 predisposes also to MS by monitoring carrier frequency of the Finnish PLOSL mutation in Finnish MS cases and by studying DAP12 and TREM2 in MS by linkage and association. To conclude, the DAP12-TREM2 complex unlikely has a role in genetic susceptibility of MS.

We analyzed whether genetic variation of alpha-synuclein modulates the extent of neuropathological changes in a population-based autopsied sample of 272 elderly Finns. None of the 11 markers was associated with the extent of neocortical beta-amyloid pathology. The intron 4 marker rs2572324 was associated with the extent of neurofibrillary pathology (p = 0.0006, permuted p = 0.004; Braak stages IV-VI vs 0-II). The same variant also showed a trend for association with neocortical Lewy-related pathology. These results suggest for the first time that variation of alpha-synuclein modulates neurofibrillary tau pathology and support the recent observations of an interaction of alpha-synuclein and tau in neurodegeneration.

We performed a nation-wide study on geographical variation in the incidence and prevalence of medicated parkinsonism among the Finns agedor =30 years using Bayesian spatial conditional autoregressive models. Registry of reimbursed medication for parkinsonism and a prescription database of purchase of these drugs were used to identify the study subjects. They were located by the map coordinates of the place of residence and aggregated into regular 100 km(2) grid cells. A total of 7,190 incident and 10,616 prevalent cases were found. The age-adjusted annual incidence was 32.6/100,000 (95% HDR 31.8-33.4) during the years 1995 to 2000 and prevalence was 268/100,000 (95% HDR 263-274) in 2000. The male to female ratio was 1.45 (95% HDR 1.39-1.51) in incidence and 1.54 (95% HDR 1.47-1.61) in prevalence. There was strong evidence for geographic variation in incidence and prevalence. A zone with high incidence and prevalence was identified in the eastern and central part of Finland. There was no evidence for difference in incidence and prevalence between urban and rural areas. The marked (more than two-fold) geographic variation can hardly be caused solely by practices of the registration and collection of data on diagnosis or by methodological issues, but rather suggests to geographic variation in protective and predisposing factors of Parkinsonism in Finland.

Background: IRF5 is a transcription factor involved both in the type I interferon and the toll-like receptor signalling pathways. Previously, IRF5 has been found to be associated with systemic lupus erythematosus, rheumatoid arthritis and inflammatory bowel diseases. Here we investigated whether polymorphisms in the IRF5 gene would be associated with yet another disease with features of autoimmunity, multiple sclerosis (MS). Methods: We genotyped nine single nucleotide polymorphisms and one insertion-deletion polymorphism in the IRF5 gene in a collection of 2337 patients with MS and 2813 controls from three populations: two case-control cohorts from Spain and Sweden, and a set of MS trio families from Finland. Results: Two single nucleotide polymorphism (SNPs) (rs4728142, rs3807306), and a 5 bp insertion-deletion polymorphism located in the promoter and first intron of the IRF5 gene, showed association signals with values of p

Objective: Dysfunction of mitochondrial DNA polymerase gamma (POLG) has been recently recognized as an important cause of inherited neurodegenerative diseases. We have reported dominant and recessive inheritance of parkinsonism, mitochondrial myopathy, and premature amenorrhea in five ethnically distinct families with POLG1 mutations. This prompted us to carry out a detailed analysis of the coding region and intron-exon boundaries of POLG1 in Finnish patients with idiopathic sporadic Parkinson disease (PD) and in nonparkinsonian controls. Methods: The coding region of POLG1 was analyzed in 140 Finnish patients with PD and their 127 spouses as age- and ethnically matched controls. Further, we analyzed the intragenic CAG-repeat region of POLG1 in 126 additional patients with nonparkinsonian neurologic disorders and in 516 Finnish population controls. Results: We found clustering of rare variants of the POLG1 CAG-repeat, encoding a polyglutamine tract, in Finnish patients with idiopathic PD as compared to their spouses ( p = 0.003; OR 3.01, 95% CI 1.35 to 6.71), population controls ( p = 0.001; OR 2.45, 95% CI 1.45 to 4.14), and patients with nonparkinsonian neurologic disorders ( p = 0.05, OR 1.98, 95% CI 0.97 to 4.05). We found several amino acid substitutions, none of them associating with PD. These included a previously parkinsonism-associated POLG variant Y831C, found in one patient with PD, but also in five controls, suggesting that it is a neutral amino acid polymorphism. Conclusions: Our results suggest that POLG polyglutamine tract variants should be considered as a predisposing genetic factor in idiopathic sporadic Parkinson disease.

This study presents a clinical report of the Finnish chromosome t(18q; 10p) translocation family with an overview of eight other selected immunoglobulin A (IgA)-deficient 18q deletion (18q-) patients from seven published articles. The family members show features common to 18q- syndrome such as mental retardation, multiple facial dysmorphism, foot/hand deformities, abnormal myelination of brain white matter, and a spectrum of immunological/infectious disorders including IgA deficiency (IgAD). Genotype-phenotype correlation study of the unbalanced t(18q-; 10p+) translocation family members and other 18q- syndrome reports led to definition of a potential susceptibility gene locus for IgAD at distal region of 18q22.3-q23 between markers D18S812-18qter. The haplo-insufficiency of the 18q22.3-q23 gene region is suggested to be a cause of the IgAD phenotype in 18q- individuals. This 7 Mb IgAD critical region shows significant association with susceptibility region for celiac disease that is frequently connected to IgAD.

Background The C9ORF72 expansion is one of the most common genetic etiologies observed with behavioural variant frontotemporal dementia (bvFTD). Revised diagnostic criteria for bvFTD (FTDC) were recently introduced but only a few studies have evaluated the accuracy of these criteria. Objective The objective of the study was to evaluate the applicability of the FTDC criteria and assess the psychiatric history of these patients. Methods The study examined 36 patients carrying the C9ORF72 expansion and suffering from bvFTD (N = 32) or from bvFTD with motor neuron disease (bvFTD-MND, N = 4). Neuropsychological, neuropsychiatric, structural brain imaging and PET/SPECT data were evaluated. Results We found 0.75 sensitivity (SD 0.44, 95% CI 0.57-0.87) for possible bvFTD and 0.64 (SD 0.44, 95% CI 0.57-0.87) for probable bvFTD. The sensitivity was even higher in bvFTD patients without MND, i.e., 0.81 for possible bvFTD and 0.69 for probable bvFTD. PET/SPECT was normal in 17.6% of scanned patients with bvFTD. A history of psychiatric symptoms (psychotic and/or mood symptoms) was detected in 61% of cases. Conclusions The FTDC possible and probable bvFTD criteria seem to identify the majority of the C9ORF72 expansion carriers with bvFTD, even though they exhibit only a limited number of behavioral criteria but a significant amount of psychiatric symptoms. The presence of a normal PET/SPECT does not exclude the possibility the C9ORF72 associated bvFTD.

To the Editor: The strongest variant (rs7702187) associated with Parkinson disease (PD [MIM 168600]) reported in the whole-genome association study by Maraganore et al.1 was evaluated in two independent case-control series of patients from Finland and Taiwan, as were four other variants located within SEMA5A (MIM 609297). The Finnish series comprised 146 patients with sporadic PD (mean age 67.2 years, range 38–88 years; 41% women) and 135 neurologically normal, healthy control subjects (mean age 65.8 years, range 37–80 years; 64% women). All individuals were recruited from the neurological outpatient clinics of the Helsinki University Central Hospital and Seinajoki Central Hospital. The Taiwanese series consisted of 303 patients with sporadic PD (mean age 61.9 years, range 24–91 years; 46.2% women) and 171 control individuals (mean age 60.1 years, range 31–86 years; 43.9% women). Patients were selected from the neurological clinic of Chang-Gung Memorial Hospital. Individuals with evidence of secondary parkinsonism or with atypical features such as early dementia, ophthalmoplegia, early autonomic failure, and pyramidal signs were not included in this study. All patients included in the study fulfilled PD diagnosis criteria.2 All participants signed an informed consent form. Taqman Assays-by-Design SNP Genotyping Assays (Applied Biosystems) were employed for allelic discrimination of all SNPs. Differences in allele and genotype distributions were analyzed using the χ2 test, and two-tailed P values are presented. Haplotype frequency comparisons between cases and controls were performed with PHASE version 2.1 software.3 One thousand permutations were performed for each comparison. The COCAPHASE module of the UNPHASED statistical package was used for linkage-disequilibrium (LD) analyses.4 Power calculations were performed with PS version 2.1.30.5 Allele and genotype frequency information for each of the markers is shown in table 1. None of the markers showed any significant association with disease in the Finnish series. However, we were able to replicate the reported association with marker rs7702187 in the Taiwanese cohort (odds ratio [OR] = 1.53, 95% CI 1.12–2.10, P=.007). Genotype analysis showed that individuals homozygous for the A allele had a significantly decreased risk of PD compared with those heterozygous or homozygous for the T allele (OR = 0.60, 95% CI 0.41–0.88, P=.009). A significant association was also found for the rs3798097 marker, which is located in the 5′ UTR region of SEMA5A (OR for the C allele was 1.71, 95% CI 1.06–2.73, P=.025). Table 1 Genotype and Allele Frequency Distribution of the Polymorphisms Analyzed across SEMA5A on Chromosome 5 Both populations showed a complete lack of LD for any pairs of neighboring polymorphisms (all D′ values were

Genetic susceptibility to multiple sclerosis is associated with genes of the major histocompatibility complex (MHC), particularly HLA-DRB1 and HLA-DQB1 (ref. 1). Both locus and allelic heterogeneity have been reported in this genomic region. To clarify whether HLA-DRB1 itself, nearby genes in the region encoding the MHC or combinations of these loci underlie susceptibility to multiple sclerosis, we genotyped 1,185 Canadian and Finnish families with multiple sclerosis (n = 4,203 individuals) with a high-density SNP panel spanning the genes encoding the MHC and flanking genomic regions. Strong associations in Canadian and Finnish samples were observed with blocks in the HLA class II genomic region (P < 4.9 x 10(-13) and P < 2.0 x 10(-16), respectively), but the strongest association was with HLA-DRB1 (P < 4.4 x 10(-17)). Conditioning on either HLA-DRB1 or the most significant HLA class II haplotype block found no additional block or SNP association independent of the HLA class II genomic region. This study therefore indicates that MHC-associated susceptibility to multiple sclerosis is determined by HLA class II alleles, their interactions and closely neighboring variants.

Objective: To assess the accuracy and clinical usefulness of [123I]s-CIT (2s-carbomethoxy-3s-(4-iodophenyl)tropane) SPECT in the differential diagnosis of Parkinson's disease. Subjects: 185 consecutive patients with symptoms of movement disorder were studied. The diagnoses were Parkinson's disease (92), essential tremor (16), vascular parkinsonism (15), various Parkinson plus syndromes (P+) (12), dementia with Lewy bodies (DLB) (5), dystonia (5), drug induced movement disorder (12), and other diagnoses (8). A reference group (psychogenic parkinsonism) comprised 20 subjects with complaints suggesting extrapyramidal disease but with no unequivocal signs on clinical examination and no abnormalities on brain imaging. Results: s-CIT uptake was significantly lower in the whole striatum as well as separately in the putamen and in the caudate nucleus in Parkinson's disease than in the reference group or in drug induced movement disorder, essential tremor, or dystonia. The uptake of s-CIT in the vascular parkinsonism group was heterogeneous and mean s-CIT uptake fell between the reference group and the Parkinson's disease group. In the P+ and DLB groups the striatal uptake ratios overlapped those of the Parkinson's disease group. Conclusions: [123I]s-CIT SPECT may not be as useful a tool in the clinical differential diagnosis of Parkinson's disease as was previously believed, but it was 100% sensitive and specific for the diagnosis in younger patients (age 55 years) specificity was substantially lower (68.5%). This differential specificity reflected the different distribution of differential diagnostic disorders (P+, DLB, vascular parkinsonism) in the older and younger age groups.

Background Fibroblast growth factor 20 (FGF20) is a neurotrophic factor preferentially expressed in the substantia nigra of rat brain and could be involved in dopaminergic neurons survival. Recently, a strong genetic association has been found between FGF20 gene and the risk of suffering from Parkinson's disease (PD). Our aim was to replicate this association in two independent populations. Methods Allelic, genotypic, and haplotype frequencies of four biallelic polymorphisms were assessed in 151 sporadic PD cases and 186 controls from Greece, and 144 sporadic PD patients and 135 controls from Finland. Results No association was found in any of the populations studied. Conclusion Taken together, these findings suggest that common genetic variants in FGF20 are not a risk factor for PD in, at least, some European populations.

Tyrosinase is a key enzyme in the synthesis of melanin in skin and hair and has also been proposed to contribute to the formation of neuromelanin (NM). The presence of NM, which is biochemically similar to melanin in peripheral tissues, identifies groups of neurons susceptible in Parkinson's disease (PD). Whether tyrosinase is beneficial or detrimental to neurons is unclear; whilst the enzyme activity of tyrosinase generates dopamine-quinones and other oxidizing compounds, NM may form a sink for such radical species. In the present study, we demonstrated that tyrosinase is expressed at low levels in the human brain. We found that mRNA, protein and enzyme activity are all present but at barely detectable levels. In cell culture systems, expression of tyrosinase increases neuronal susceptibility to oxidizing conditions, including dopamine itself. We related these in vitro observations to the human disease by assessing whether there was any genetic association between the gene encoding tyrosinase and idiopathic PD. We found neither genotypic or haplotypic association with three polymorphic markers of the gene. This argues against a strong genetic association between tyrosinase and PD, although the observed contribution to cellular toxicity suggests that a biochemical association is likely.

Recent data has demonstrated that mutations in PINK1, encoding PTEN-induced kinase 1, are a cause of early onset recessive parkinsonism (PARK6 locus). Common variability in genes implicated in hereditary forms of parkinsonism may be a predisposing factor in sporadic Parkinson's disease (PD). We analyzed whether six different genetic variants within and surrounding PINK1 contribute to the risk of sporadic PD in a Finnish case-control series. Our results indicate that this gene does not play a major role in the genetic predisposition to PD in this population.

The authors recently have shown that triplication of the alpha-synuclein gene (SNCA) can cause Parkinson disease (PD) and diffuse Lewy body disease within the same kindred. The authors assessed 101 familial PD probands, 325 sporadic PD cases, 65 patients with dementia with Lewy bodies, and 366 neurologically normal control subjects for SNCA multiplication. The authors did not identify any subjects with multiplication of SNCA and conclude this mutation is a rare cause of disease.

Genetic linkage studies have provided evidence for a late-onset Alzheimer's disease (AD) susceptibility locus on chromosome 21q. We have tested, in a two-stage association study, whether allelic or haplotype variation of the beta-amyloid cleaving enzyme-2 (BACE2) locus on chromosome 21q affects the risk of late-onset AD. In stage-1, an unselected population-based sample of Finns aged 85 years or over (n=515) was analysed. Neuropathologic examination including beta-amyloid load quantification was possible in over 50% (n=264) of these subjects. AD patients (n=100) and controls (n=48) were defined by modified neuropathological NIA-RI criteria. Positive associations were taken as a hypothesis, and tested in stage-2 using 483 AD families from the USA. Four single nucleotide polymorphisms (SNPs) of BACE2 gene were tested in stage-1. A SNP close to exon-6 was associated with neuropathologically verified AD (p=0.02) and also with beta-amyloid load in non-selected autopsied subjects after conditioning with APOE genotype (p=0.001). In haplotype analysis a specific, relatively common haplotype (H5) was found to associate with AD (p=0.004) and a second haplotype (H7) showed a weaker association with protection against AD (p=0.04). In stage-2, the SNP association was not replicated, whereas the haplotype H5 association was replicated (p=0.004) and a trend to association was found with the putative protective haplotype H7 (two-sided p=0.08). BACE2 haplotype association with AD in two independent datasets provides further evidence for an AD susceptibility locus on chromosome 21q within or close to BACE2.

Paraoxonase 1 (PON1) is involved in the metabolism and detoxification of insecticides and pesticides. Two polymorphisms within the gene affect the enzyme activity. One is a methionine to leucine change at position 54 (M54L) and the other is a glutamine to arginine variant at position 192 (Q192R). There are contrasting reports assessing the role of these variants in Parkinson's disease (PD). We performed a case--control association study in order to elucidate the possible contribution of variability within PON1 to the risk of sporadic PD in a Finnish population. There was no statistically significant association of the allele, genotype or haplotype distribution with PD (all P values > 0.75). Our results suggest that the M54L and Q192R polymorphisms are not major risk factors for PD in the Finnish population.

Nitric oxide is a biologic messenger molecule involved in a diverse range of physiologic processes. An exon 22 inducible nitric oxide synthase genotype has recently been reported to be protective against Parkinson disease in a European cohort. The authors confirm the protective effect of this genotype (OR = 0.5, 95% CI 0.27 to 0.93) in an independent Finnish case-control series.

Mutations in DJ-1 are a cause of autosomal recessive parkinsonism. Polymorphism of genes implicated in hereditary forms of parkinsonism may be a predisposing factor in sporadic Parkinson's disease (PD). The authors analyzed whether a polymorphism (g.168_185del) within exon 1 of DJ-1 contributes to the risk of sporadic PD in a Finnish case-control series. This gene does not play a major role in the genetic predisposition to PD in this population.

Intercellular adhesion molecule-1 (ICAM-1) is involved in the pathogenesis of multiple sclerosis (MS), whereas sequence variations in the ICAM-1 gene could potentially be responsible for the genetic susceptibility to MS. We studied an association of MS with the 13,848A>G (K469E) polymorphism of the ICAM-1 gene in Finnish and Spanish cases and controls and affected families. An increased risk for the AA (Lys(469)/Lys(469)) genotype was found in both populations. The effect observed was found to be strongest among the HLA-DQB1*0602-positive subjects, which implies genetic heterogeneity of MS. Meta-analysis of all published datasets supports increased risk of MS for the ICAM-1 Lys(469) homozygotes (relative risk = 1.3, p = 0.002).

Objective: To compare the secular trends and geographical differences in the incidence of relapsing-remitting (RRMS) and primary progressive multiple sclerosis (PPMS) in Finland, and to draw inferences about aetiological differences between the two forms of the disease. Methods: New multiple sclerosis cases in southern Uusimaa and the western districts Vaasa and Seinajoki of Finland in 1979–1993 were verified from hospital records and classified into RRMS and PPMS. Patients met the Poser criteria for definite multiple sclerosis or otherwise satisfied the criteria for PPMS. Disease course was categorised by the same neurologist. Crude and age adjusted incidence in 1979–1993 was estimated. Results: During 1979–1993 the age adjusted incidence was 5.1 per 100 000 person-years in Uusimaa, 5.2 in Vaasa, and 11.6 in Seinajoki. The rates in Uusimaa remained stable, while a decrease occurred in Vaasa and an increase in Seinajoki. Between 1979–86 and 1987–93 the incidence of PPMS increased in Seinajoki from 2.6 to 3.7 per 105 and decreased in Vaasa from 1.9 to 0.2 per 105; the trends were similar for RRMS. Conclusions: There are significant differences in secular trends for multiple sclerosis incidence in Finland by geographical area, but these are similar for PPMS and RRMS. The recent changes point to locally acting environmental factors. The parallel incidence trends for RRMS and PPMS suggest similar environmental triggers for the two clinical presentations of multiple sclerosis.

We analyzed the HLA class II haplotypes in 249 Finnish nuclear families and compared the frequencies of parental haplotypes transmitted or non-transmitted to multiple sclerosis (MS) patients. The most important predisposing haplotype was DRB1*15-DQB1*0602 (P

Importance Considerable advances have been made in our understanding of the genetics underlying amyotrophic lateral sclerosis (ALS). Nevertheless, for the majority of patients who receive a diagnosis of ALS, the role played by genetics is unclear. Further elucidation of the genetic architecture of this disease will help clarify the role of genetic variation in ALS populations. Objective To estimate the relative importance of genetic factors in a complex disease such as ALS by accurately quantifying heritability using genome-wide data derived from genome-wide association studies. Design, Setting, and Participants We applied the genome-wide complex trait analysis algorithm to 3 genome-wide association study data sets that were generated from ALS case-control cohorts of European ancestry to estimate the heritability of ALS. Cumulatively, these data sets contained genotype data from 1223 cases and 1591 controls that had been previously generated and are publically available on the National Center for Biotechnology Information database of genotypes and phenotypes website (http://www.ncbi.nlm.nih.gov/gap). The cohorts genotyped as part of these genome-wide association study efforts include the InCHIANTI (aging in the Chianti area) Study, the Piemonte and Valle d’Aosta Register for Amyotrophic Lateral Sclerosis, the National Institute of Neurological Disorders and Stroke Repository, and an ALS specialty clinic in Helsinki, Finland. Main Outcomes and Measures A linear mixed model was used to account for all known single-nucleotide polymorphisms simultaneously and to quantify the phenotypic variance present in ostensibly outbred individuals. Variance measures were used to estimate heritability. Results With our meta-analysis, which is based on genome-wide genotyping data, we estimated the overall heritability of ALS to be approximately 21.0% (95% CI, 17.1-24.9) (SE = 2.0%), indicating that additional genetic variation influencing risk of ALS loci remains to be identified. Furthermore, we identified 17 regions of the genome that display significantly high heritability estimates. Eleven of these regions represent novel candidate regions for ALS risk. Conclusions and Relevance We found the heritability of ALS to be significantly higher than previously reported. We also identified multiple, novel genomic regions that we hypothesize may contain causative risk variants that influence susceptibility to ALS.

Background. Attrition is a major cause of potential bias in longitudinal studies and clinical trials. Attrition rate above 20% raises concern of the reliability of the results. Few studies have looked at the factors behind attrition in follow-ups spanning decades. Methods. We analyzed attrition and associated factors of a 30-year follow-up cohort of subjects who were born with perinatal risks for neurodevelopmental disorders. Attrition rates were calculated at different stages of follow-up and differences between responders and non-responders were tested. To find combinations of variables influencing attrition and investigate their relative importance at birth, 5, 9, 16 and 30 years of follow-up we used the random forest classification. Results. Initial loss of potential participants was 13%. Attrition was 16% at five, 24% at nine, 35% at 16 and 46% at 30 years. The only group difference that emerged between responders and non-responders was in socioeconomic status (SES). The variables identified by random forest classification analysis were classified into Birth related, Development related and SES related. Variables from all these categories contributed to attrition, but SES related variables were less important than birth and development associated variables. Classification accuracy ranged between 0.74 and 0.96 depending on age. Discussion. Lower SES is linked to attrition in many studies. Our results point to the importance of the growth and development related factors in a longitudinal study. Parents’ decisions to participate depend on the characteristics of the child. The same association was also seen when the child, now grown up, decided to participate at 30 years. In addition, birth related medical variables are associated with the attrition still at the age of 30. Our results using a data mining approach suggest that attrition in longitudinal studies is influenced by complex interactions of a multitude of variables, which are not necessarily evident using other multivariate techniques.

A hexanucleotide repeat expansion in the chromosome 9 open reading frame 72 gene (C9orf72) was recently identified as the most common genetic cause of frontotemporal dementia/amyotrophic lateral sclerosis. Here we describe the clinical, pathologic, and genetic features of a Finnish C9orf72 expansion carrier, who developed a dysplastic gangliocytoma (Lhermitte-Duclos disease), a rare hamartoma/overgrowth syndrome of cerebellar granule cells associated with mutations in the phosphatase and tensin homolog gene. In addition to the dysplastic gangliocytoma, the patient showed typical transactive response DNA-binding protein with Mr 43 kD (TDP-43) pathology mainly in the cortex and the substantia nigra and numerous p62-positive/TDP-43-negative inclusions in the cerebellar granule cells. His sister carried the same gene defect and showed a similar type of TDP-43/p62 pathology in her brain. Our findings confirm that the clinical and pathologic picture of C9orf72 mutation carriers is more heterogeneous than originally thought and warrants further studies on the possible involvement of phosphatase and tensin homolog gene pathway in the specific cerebellar granule cell pathology associated with C9orf72 expansion.

Variants of the lipoprotein lipase (LPL) gene have been shown to influence serum lipid levels, risk of coronary heart disease and, as found recently, risk of clinical ischaemic cerebrovascular disease. Here we tested for an association between brain infarction and two common polymorphisms of the LPL gene, Ser447Ter and Asn291 Ser.To avoid ascertainment and selection bias involved in many association studies, we compared the distribution of these polymorphisms in neuropathologically verified patients (n = 119) vs controls (n = 133) derived from a prospective, population-based study (the Vantaa 85+ study).The LPL Ter447 variant was negatively associated with neuropathologically verified brain infarcts (P = 0.006), and even more strongly with small brain infarcts (P = 0.004). In addition, we found that the Ter447 variant was associated with higher serum HDL chblesterol (P = 0.004) and lower triglyceride levels (P= 0.003), and that it was negatively associated with pathologically verified severe coronary artery disease (P=0.001) in the Vantaa 85+ study sample. The Asn291Ser polymorphism was not significantly associated with brain infarction.The Ter447 variant of LPL is associated with decreased risk of brain infarction and coronary artery disease in our very elderly population.

Background A hexanucleotide repeat expansion, in the chromosome 9 open reading frame 72 gene (C9orf72), has been identified the most common genetic cause of FTD/ALS. Here we describe the clinical, pathologic and genetic features of a Finnish C9orf72 expansion carrier, who developed a dysplastic gangliocytoma, a rare hamartoma of cerebellar granule cells, associated with PTEN mutations. In addition to the dysplastic gangliocytoma, the patient showed TDP43-pathology in the cortex and in the substantia nigra, and p62-positive/TDP43-negative inclusions in the cerebellar granule cells. His sister carried the same gene defect and showed similar type of TDP43/p62-pathology in her brain. Our findings confirm the clinical and pathological picture of C9orf72 mutation carriers is more heterogeneous than originally thought and warrant further studies on the possible involvement of PTEN pathway in the specific cerebellar granule cell pathology associated with C9orf72 expansion.

We show here that alternative splicing influences the polarized secretion of amyloid precursor protein (APP) as well as the release of its proteolytic 3-4-kDa fragments betaA4 and p3. In Madin-Darby canine kidney II cells stably transfected with various APP isoforms and APP mutants, APPsec was consistently secreted basolaterally. In contrast, Madin-Darby canine kidney II cells transfected with L-APP677, which occurs naturally by alternative splicing of exon 15, secreted this isoform both apically and basolaterally, while maintaining the basolateral sorting of endogenous APPsec. This suggests that the alternative splicing of APP exon 15 modulates the polarized sorting of secretory APP. The same alternative splicing event also decreased the production of betaA4 relative to p3. This is the first example of alternative splicing regulating polarized trafficking of a secretory protein.

The aim of this study was to investigate the proteolytic processing of the amyloid precursor protein (APP) in polarized primary cultures of hippocampal neurons. We have used the Semliki Forest virus (SFV) vector to express human APP695 in hippocampal neurons, sympathetic ganglia, and glial cells. The latter two cells secrete little or no APP, whereas hippocampal neurons secrete two forms of APP695, which differ in sialic acid content and in their kinetic appearance in the culture medium. In addition, rat hippocampal neurons expressing human APP produced significant amounts of the 4 kDa peptide beta A4. After 3 hr of metabolic labeling, the relative amount of beta A4 peptide to total cellular APP was 5.3%. Fibroblasts expressing APP695 using the same SFV vector mainly produced a related 3 kDa p3 peptide, a nonamyloidogenic fragment. Remarkably, the hippocampal neurons also produced significant amounts of beta A4-containing C-terminal fragments (10–12 kDa) intracellularly. Radiosequencing showed that these fragments were created at a previously described beta-secretase cleavage site and at a cleavage site 12 residues from the N terminus of the beta A4 domain (Thr584 of APP695), which we named delta-cleavage. Based on the observation that mature hippocampal neurons produce two potentially amyloidogenic fragments and secrete substantial amounts of beta A4 when expressing human APP, our results strengthen the hypothesis that neurons play a central role in the process of beta A4 deposition in cases of Alzheimer's disease and in aged primates.

One of the major challenges in genetic linkage analyses is the study of complex diseases. We demonstrate here the use of two-locus linkage analysis in multiple sclerosis (MS), a multifactorial disease with a complex mode of inheritance. In a set of Finnish multiplex families, we have previously found evidence for linkage between MS susceptibility and two independent loci, the myelin basic protein gene (MBP) on chromosome 18 and the HLA complex on chromosome 6. This set of families provides a unique opportunity to perform linkage analysis conditional on two loci contributing to the disease. In the two-trait-locus/two-marker-locus analysis, the presence of another disease locus is parametrized and the analysis more appropriately treats information from the unaffected family members than single-disease-locus analysis. As exemplified here in MS, the two-locus analysis can be a powerful method for investigating susceptibility loci in complex traits, best suited for analysis of specific candidate genes, or for situations in which preliminary evidence for linkage already exists or is suggested.

Nature and nurture are not separate. Instead it is important to investigate the interplay between genes and environment and how they influence on another. To an important degree, genetic effects on behavior come about because they either influence the extent to which the individual is likely to be exposed to individual differences in environmental risk or they affect how susceptible the individual is to environmental adversities.The current inability to explain or predict which genetically predisposed individuals will finally become schizophrenic has forced us to confront our ignorance of the precise mechanism and mode of the transmission of this disorder. Zubin's proposal to view the schizophrenic as a vulnerable individual who develops a temporary episode only under certain provocations can help place the controversy in proper perspective. Vulnerability (predisposition, diathesis) to schizophrenia can be defined as the individual's characteristic treshold beyond which stressful events produce decompensation manifest in the clinically diagnosable symptom picture.

Background: We and others recently identified the gene underlying PARK8 linked Parkinson’s disease (PD). This gene, LRRK2 , contains mutations that cause an autosomal dominant PD, including a mutation, G2019S, which is the most common PD causing mutation identified to date. Common genetic variability in genes that contain PD causing mutations has previously been implicated as a risk factor for typical sporadic disease. Methods: We undertook a case-control association analysis of LRRK2 in two independent European PD cohorts using 31 tagging single nucleotide polymorphisms (tSNPs) and five potentially functional SNPs. To assess the structure of this locus in different populations, we have performed linkage disequilibrium (LD) analysis using these variants in a human diversity panel. Results: We show that common genetic variability in LRRK2 is not associated with risk for PD in the European populations studied here. We also show inter-population variability in the strength of LD across this locus. Conclusions: To our knowledge this is the first comprehensive analysis of common variability within LRRK2 as a risk factor for PD.

Alcohol dehydrogenases (ADHs) may be involved in the pathogenesis of neurodegenerative disorders because of their multiple roles in detoxification pathways and retinoic acid synthesis. In a previous study, significant association of an ADH class IV allele with Parkinson disease (PD) was found in a Swedish sample.The previously associated single-nucleotide polymorphism plus 12 further polymorphisms in the ADH cluster on human chromosome 4q23 were screened for association in an extension of the original sample that now included 123 Swedish PD patients and 127 geographically matched control subjects. A rare nonsense single-nucleotide polymorphism in ADH1C (G78stop, rs283413) was identified in 3 of these patients but in no controls. To obtain sufficient power to detect a possible association of this rare variant with disease, we screened a large international sample of 1076 PD patients of European ancestry and 940 matched controls.The previously identified association with an ADH class IV allele remained significant (P.02) in the extended Swedish study. Furthermore, in the international collaboration, the G78stop mutation in ADH1C was found in 22 (2.0%) of the PD patients but only in 6 controls (0.6%). This association was statistically significant (chi(2)(1) = 7.5; 2-sided P = .007; odds ratio, 3.25 [95% confidence interval, 1.31-8.05]). In addition, the G78stop mutation was identified in 4 (10.0%) of 40 Caucasian index cases with PD with mainly hereditary forms of the disorder.Findings presented herein provide further evidence for mutations in genes encoding ADHs as genetic risk factors for PD.

Hospitalization rates of monozygotic (MZ) and dizygotic (DZ) twin pairs in Finland were compared for schizophrenia, neuroses, and alcoholism. Record-linkage of hospital records and death certificates for the years 1972-1979 was carried out for persons in the Finnish Twin Cohort (16,649 like-sexed twin pairs). The ratio of the number of observed vs that of expected concordant pairs and the ratio of concordance rates between MZ and DZ pairs were greater among males than females, and greater among young (40 years old or less) than among older pairs. The highest difference was found in schizophrenia and the lowest in neuroses. Pairwise concordance rates for schizophrenia (11.0% for MZ and 1.8% for DZ) seem to indicate great environmental influence (high proportion of discordant pairs) with apparent genetic liability (6.1-fold ratio in concordance between MZ and DZ pairs). In neurotic disorders, the difference of pairwise concordance rates between MZ and DZ pairs (6.8% vs 4.0%) was quite low, not strongly supporting a genetic hypothesis. Of the MZ pairs concordant for psychiatric hospitalization, 47% had lived together for their whole life time; of those discordant, 16% lived together. The corresponding figures for DZ pairs were 18% and 15%. The effect of intrapair relationships in disease-concordant pairs should be taken into account when evaluating the effect of genetic and environmental factors in psychiatric disorders.

Summary Multiple sclerosis (MS) is a neurological, demyelinating disorder with a putative autoimmune etiology. It is thought to be a multifactorial disease with a complex mode of inheritance. Here we report the results of a two-stage genomewide scan for loci predisposing to MS. The first stage of the screen, with a low-resolution map, was performed in a selection of 16 pedigrees collected from an isolated Finnish population. Multipoint, nonparametric linkage analysis of the 328 markers did not reveal statistically significant results. However, 10 slightly interesting regions ( P =.1–.15) emerged, including our previous findings of the HLA complex on 6p21 and a putative locus on 5p14-p12. Eight of these novel regions were further analyzed by use of denser marker maps, in the second stage of the scan. For the chromosomal regions 4cen, 11tel, and 17q, the statistical significance increased, but not conclusively; for 2q32 and 10q21, the statistical significance did not change. Accordingly, genotyping of the high-density markers in these regions was performed, and the data were analyzed by use of two-point, parametric linkage analysis using the complete pedigree information of the 21 Finnish multiplex families. We detected suggestive evidence for a predisposing locus on chromosomal region 17q22-q24. Several markers on 17q22-q24 yielded positive LOD scores, with the maximum LOD score ( Z max ) occurring with D17S807 ( Z max =2.8, θ=.04; dominant model. Interestingly, a suggestive linkage between MS and the markers on 17q22-q24 was also revealed by a recent genomewide scan in MS families from the United Kingdom.

The proteolytic fragments derived from the amyloid precursor protein (APP) in primary cultures of rat hippocampal neurons were analyzed by two-dimensional gel electrophoresis. The Semliki Forest Virus expression vector was used to express human APP695 and a mutant form associated with familial Alzheimer's disease (APP-FAD670/671). Hippocampal neurons expressing wtAPP695 or APP-FAD670/671 secrete at least six APP fragments of 100–110 kDa with isoelectric focusing points ranging from 4.5 to 4.0. The heterogeneity of the secreted APP forms is shown to be in part due to differences in glycosylation. In contrast to wtAPP695, neurons producing the APP-FAD670/ 671 variant did not secrete detectable amounts of secretory APP derived from cleavage within the amyloid βA4 domain. This result suggests that there is little α-secretase cleavage in neurons expressing the APP-FAD670/671 mutant.

Little is known about the quality of polyclonal antibody responses in COVID-19 patients, and how it correlates with disease severity or patients' prior exposure to other pathogens. The whole polyclonal antibody repertoire in a retrospective cohort of 538 individuals was mapped against SARS-CoV-2 spike (S) glycoprotein, the main target of antibody immune responses in SARS-CoV-2 infection. Bioinformatic predictions identified 15 major B cell epitopes for S of SARS-CoV-2. Several epitopes localised in RBD of S including those spanning the ACE2-binding site, the highly conserved cryptic epitope of the neutralizing antibody of SARS-CoV, and fusion/entry domains of HR1 and HR2 of S protein of SARS-CoV-2. Intriguingly, some of these epitopes have cross-reactivity to antigens of common pathogens, potentially affecting SARS-CoV-2 infection outcome. High level of anti-Spike SARS-CoV-2 seroreactivity in populations with no history of exposure to SARS-CoV-2 is of clinical relevance and could underpin better understanding of COVID-19 pathophysiology in different populations and provide a blueprint for design of effective vaccines and developing better strategies for antibody testing.

We and others have previously identified two distinct haplotypes of the TAU gene in Caucasian populations. In this study, we have assessed whether these haplotypes show an association with Alzheimer's disease in a variety of populations. They do not. These data are consistent with the view that the involvement of TAU in Alzheimer's disease is a downstream event.

Multiple sclerosis (MS) is a chronic disease of the central nervous system responsible for a large portion of neurological disabilities in young adults. Similar to what occurs in numerous complex diseases, both unknown environmental factors and genetic predisposition are required to generate MS. We ascertained a set of 63 Finnish MS families, originating from a high-risk region of the country, to identify a susceptibility gene within the previously established 3.4-Mb region on 17q24. Initial single nucleotide polymorphism (SNP)-based association implicated PRKCA (protein kinase C alpha) gene, and this association was replicated in an independent set of 148 Finnish MS families (p = 0.0004; remaining significant after correction for multiple testing). Further, a dense set of 211 SNPs evenly covering the PRKCA gene and the flanking regions was selected from the dbSNP database and analyzed in two large, independent MS cohorts: in 211 Finnish and 554 Canadian MS families. A multipoint SNP analysis indicated linkage to PRKCA and its telomeric flanking region in both populations, and SNP haplotype and genotype combination analyses revealed an allelic variant of PRKCA, which covers the region between introns 3 and 8, to be over-represented in Finnish MS cases (odds ratio = 1.34, 95% confidence interval 1.07–1.68). A second allelic variant, covering the same region of the PRKCA gene, showed somewhat stronger evidence for association in the Canadian families (odds ratio = 1.64, 95% confidence interval 1.39–1.94). Initial functional relevance for disease predisposition was suggested by the expression analysis: The transcript levels of PRKCA showed correlation with the copy number of the Finnish and Canadian “risk” haplotypes in CD4-negative mononuclear cells of five Finnish multiplex families and in lymphoblast cell lines of 11 Centre d'Etude du Polymorphisme Humain (CEPH) individuals of European origin., Synopsis Complex diseases such as multiple sclerosis (MS) likely result from problems in networks of interactions between several genes and largely unidentified environmental and lifestyle factors. Identification of MS-specific genes has been challenging. HLA-DRB1*15 is the only consistent locus observed in most populations; however, the recent genome scan on more than 700 European families implicated 17q as a second-best MS locus [12]. Since MS families from the high-risk region of Finland initially revealed linkage to 17q, the authors used the regionally ascertained set of 63 families to identify a MS predisposing gene within a major non–HLA locus on 17q. The initial association was observed with single nucleotide polymorphisms (SNPs) located in intron 3 of the PRKCA (protein kinase C alpha) gene in Finnish MS families and replicated in an independent set of 148 MS families from Finland and 554 from Canada, two populations with a different genetic background. Combining the data of two SNP variants revealed two allele combinations of PRKCA, which were over-represented in Finnish or Canadian MS cases (odds ratio = 1.34, 95% confidence interval, 1.07–1.68, and odds ratio = 1.64, 95% confidence interval 1.39–1.94, respectively). Linkage and association of the PRKCA gene, encoding a regulator of immune responses, in two populations imply its involvement in the etiology of MS.

Although association between multiple sclerosis (MS) and HLA-DR2,DQw6 has been well documented, family studies have not established linkage to HLA. Here we have (1) carried out an HLA-DQA1, -DQB1 association study in unrelated patients and controls, and (2) analyzed linkage between MS and HLA in multiplex families using both nonparametric and parametric methods. The subjects and families were derived from the genetically homogeneous Finnish population, and 14 of the 21 families came from a high-risk area with exceptional familial clustering of cases. In the association study, the frequencies of the alleles DQA1*0102 and DQB1*0602 (encoding DR2-associated DQw6 antigen) were significantly increased in MS patients compared to controls. In the families, we observed that the segregation of MS with DQA1*0102 and DQB1*0602 was not HLA haplotype specific, i.e., these alleles were frequently transmitted to MS relatives on different parental haplotypes. Consequently, we found strong evidence for linkage between MS and HLA only when the haplotype-independent segregation of the MS-associated alleles was controlled. This observation may partially explain the lack of linkage evidence in previous family studies. The highest LOD scores were obtained to the DQA1 locus (LODmax = 6.43, theta = 0.00). The linkage analyses suggest that both the patients' HLA haplotypes may contribute to MS susceptibility. In one of a patient's haplotypes, the susceptibility locus was closely associated with DQA1*0102 and DQB1*0602, whereas in the other haplotype no association with any of the individual candidate loci was found. These results demonstrate, for the first time, a close linkage between MS and HLA, and raise the possibility of distinct HLA-linked susceptibility genes in MS.

We and others have recently reported an association between amyotrophic lateral sclerosis (ALS) and single nucleotide polymorphisms on chromosome 9p21 in several populations. Here we show that the associated haplotype is the same in all populations and that several families previously shown to have genetic linkage to this region also share this haplotype. The most parsimonious explanation of these data are that there is a single founder for this form of disease. (C) 2012 Elsevier Inc. All rights reserved.