Terhi Peuralinna

A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD

The chromosome 9p21 amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) locus contains one of the last major unidentified autosomal-dominant genes underlying these common neurodegenerative diseases. We have previously shown that a founder haplotype, covering the MOBKL2b, IFNK, and C9ORF72 genes, is present in the majority of cases linked to this region. Here we show that there is a large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72 on the affected haplotype. This repeat expansion segregates perfectly with disease in the Finnish population, underlying 46.0% of familial ALS and 21.1% of sporadic ALS in that population. Taken together with the D90A SOD1 mutation, 87% of familial ALS in Finland is now explained by a simple monogenic cause. The repeat expansion is also present in one-third of familial ALS cases of outbred European descent, making it the most common genetic cause of these fatal neurodegenerative diseases identified to date.

Senile systemic amyloidosis affects 25% of the very aged and associates with genetic variation in alpha2-macroglobulin and tau: a population-based autopsy study.

Background. Senile systemic amyloidosis (SSA) is characterized by deposition of wild‐type transthyretin (TTR)‐based amyloid in parenchymal organs in elderly individuals. Previously, no population‐based studies have been performed on SSA. Methods. Here we have studied the prevalence and risk factors for SSA in a Finnish autopsied population aged 85 or over, as part of the population‐based Vantaa 85+ Autopsy Study (n = 256). The diagnosis of SSA was based on histological examination of myocardial samples stained with Congo red and anti‐TTR immunohistochemistry. The genotype frequencies of 20 polymorphisms in 9 genes in subjects with and without SSA were compared. Results. The prevalence of SSA was 25%. SSA was associated with age, myocardial infarctions, the G/G (Val/Val) genotype of the exon 24 polymorphism in the alpha2‐macroglobulin (α2M), and the H2 haplotype of the tau gene (P‐values 0.002, 0.004, 0.042, and 0.016). Conclusion. This population‐based study shows that SSA is very common in old individuals, affecting one‐quarter of people aged over 85 years. Myocardial infarctions and variation in the genes for α2M and tau may be associated with SSA.

The chromosome 9 ALS and FTD locus is probably derived from a single founder

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.

POLG1 polyglutamine tract variants associated with Parkinson's disease

A possible role of allelic variation of the mitochondrial DNA polymerase gamma (POLG1) gene in Parkinsons disease (PD) has been suggested. First, POLG1 missense mutations have been found in patients with familial parkinsonism and mitochondrial myopathy. Second, increased frequency of rare alleles of the POLG1 CAG-repeat (poly-Q) has been found in Finnish idiopathic apparently sporadic PD patients, but conflicting reports exist. The POLG1 poly-Q exhibits one major allele with 10 repeats (10Q, frequency >/=80%) and several less common alleles such as 11Q (frequency 6-9%), 6Q-9Q and 12Q-14Q (frequencies <4%). It is not known, whether the poly-Q variation modulates POLG1 function. Here we sequenced the poly-Q in 641 North American Caucasian PD patients and 292 controls. Caucasian literature controls were also used. Normal allele was defined either as 10/11Q or as 10Q according to the previous literature. The frequency of the non-10/11Q alleles in cases was not significantly different from the controls. Variant alleles defined as non-10Q were significantly increased in the PD patients compared to the North American controls (17.6% vs. 12.3%, p=0.004) as well as compared to the larger set of 897 controls (17.6% vs. 13.2%, p=0.0007). These results suggest that POLG1 poly-Q alleles other than the conserved 10Q allele may increase susceptibility to PD. This finding may be attributable to a beneficial function of the 10Q repeat protein or linkage disequilibrium between the 10Q allele and another variation within or close to POLG1. Other large case-control studies and analyses on functional differences of POLG1 poly-Q variants are warranted.

Assessment of a DJ-1 (PARK7) polymorphism in Finnish PD

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.

Confirmation of the protective effect of iNOS in an independent cohort of Parkinson disease

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.

Neurofibrillary tau pathology modulated by genetic variation of alpha-synuclein

We analyzed whether genetic variation of α‐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 β‐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 α‐synuclein modulates neurofibrillary tau pathology and support the recent observations of an interaction of α‐synuclein and tau in neurodegeneration. Ann Neurol 2008

Homozygosity analysis in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) may appear to be familial or sporadic, with recognised dominant and recessive inheritance in a proportion of cases. Sporadic ALS may be caused by rare homozygous recessive mutations. We studied patients and controls from the UK and a multinational pooled analysis of GWAS data on homozygosity in ALS to determine any potential recessive variant leading to the disease. Six-hundred and twenty ALS and 5169 controls were studied in the UK cohort. A total of 7646 homozygosity segments with length >2 Mb were identified, and 3568 rare segments remained after filtering ‘common’ segments. The mean total of the autosomal genome with homozygosity segments was longer in ALS than in controls (unfiltered segments, P=0.05). Two-thousand and seventeen ALS and 6918 controls were studied in the pooled analysis. There were more regions of homozygosity segments per case (P=1 × 10−5), a greater proportion of cases harboured homozygosity (P=2 × 10−5), a longer average length of segment (P=1 × 10−5), a longer total genome coverage (P=1 × 10−5), and a higher rate of these segments overlapped with RefSeq gene regions (P=1 × 10−5), in ALS patients than controls. Positive associations were found in three regions. The most significant was in the chromosome 21 SOD1 region, and also chromosome 1 2.9–4.8 Mb, and chromosome 5 in the 65 Mb region. There are more than twenty potential genes in these regions. These findings point to further possible rare recessive genetic causes of ALS, which are not identified as common variants in GWAS.

APOE and AβPP gene variation in cortical and cerebrovascular amyloid-β pathology and Alzheimer's disease: a population-based analysis.

Cortical and cerebrovascular amyloid-β (Aβ) deposition is a hallmark of Alzheimers disease (AD), but also occurs in elderly people not affected by dementia. The apolipoprotein E (APOE) ε4 is a major genetic modulator of Aβ deposition and AD risk. Variants of the amyloid-β protein precursor (AβPP) gene have been reported to contribute to AD and cerebral amyloid angiopathy (CAA). We analyzed the role of APOE and AβPP variants in cortical and cerebrovascular Aβ deposition, and neuropathologically verified AD (based on modified NIA-RI criteria) in a population-based autopsy sample of Finns aged ≥ 85 years (Vantaa85 + Study; n = 282). Our updated analysis of APOE showed strong associations of the ε4 allele with cortical (p = 4.91 × 10-17) and cerebrovascular (p = 9.87 × 10-11) Aβ deposition as well as with NIA-RI AD (p = 1.62 × 10-8). We also analyzed 60 single nucleotide polymorphisms (SNPs) at the AβPP locus. In single SNP or haplotype analyses there were no statistically significant AβPP locus associations with cortical or cerebrovascular Aβ deposition or with NIA-RI AD. We sequenced the promoter of the AβPP gene in 40 subjects with very high Aβ deposition, but none of these subjects had any of the previously reported or novel AD-associated mutations. These results suggest that cortical and cerebrovascular Aβ depositions are useful quantitative traits for genetic studies, as highlighted by the strong associations with the APOE ε4 variant. Promoter mutations or common allelic variation in the AβPP gene do not have a major contribution to cortical or cerebrovascular Aβ deposition, or very late-onset AD in this Finnish population based study.

Genome-wide association study of neocortical Lewy-related pathology.

Dementia with Lewy bodies is an α‐synucleinopathy characterized by neocortical Lewy‐related pathology (LRP). We carried out a genome‐wide association study (GWAS) on neocortical LRP in a population‐based sample of subjects aged 85 or over.