Hannu Laaksovirta

Publications (6)74.57 Total impact

• Article: Homozygosity analysis in amyotrophic lateral sclerosis.

  Kin Mok, Hannu Laaksovirta, Pentti J Tienari, Terhi Peuralinna, Liisa Myllykangas, Adriano Chiò, Bryan J Traynor, Michael A Nalls, Nicole Gurunlian, Aleksey Shatunov, Gabriella Restagno, Gabriele Mora, P Nigel Leigh, Chris E Shaw, Karen E Morrison, Pamela J Shaw, Ammar Al-Chalabi, John Hardy, Richard W Orrell
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  ABSTRACT: 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.European Journal of Human Genetics advance online publication, 24 April 2013; doi:10.1038/ejhg.2013.59.
  European journal of human genetics: EJHG 04/2013; · 3.56 Impact Factor
• Article: Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study.

  Elisa Majounie, Alan E Renton, Kin Mok, Elise G P Dopper, Adrian Waite, Sara Rollinson, Adriano Chiò, Gabriella Restagno, Nayia Nicolaou, Javier Simon-Sanchez, [......], Carsten Drepper, Nigel Williams, Janine Kirby, Pamela Shaw, John Hardy, Pentti J Tienari, Peter Heutink, Huw R Morris, Stuart Pickering-Brown, Bryan J Traynor
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  ABSTRACT: We aimed to accurately estimate the frequency of a hexanucleotide repeat expansion in C9orf72 that has been associated with a large proportion of cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We screened 4448 patients diagnosed with ALS (El Escorial criteria) and 1425 patients with FTD (Lund-Manchester criteria) from 17 regions worldwide for the GGGGCC hexanucleotide expansion using a repeat-primed PCR assay. We assessed familial disease status on the basis of self-reported family history of similar neurodegenerative diseases at the time of sample collection. We compared haplotype data for 262 patients carrying the expansion with the known Finnish founder risk haplotype across the chromosomal locus. We calculated age-related penetrance using the Kaplan-Meier method with data for 603 individuals with the expansion. In patients with sporadic ALS, we identified the repeat expansion in 236 (7·0%) of 3377 white individuals from the USA, Europe, and Australia, two (4·1%) of 49 black individuals from the USA, and six (8·3%) of 72 Hispanic individuals from the USA. The mutation was present in 217 (39·3%) of 552 white individuals with familial ALS from Europe and the USA. 59 (6·0%) of 981 white Europeans with sporadic FTD had the mutation, as did 99 (24·8%) of 400 white Europeans with familial FTD. Data for other ethnic groups were sparse, but we identified one Asian patient with familial ALS (from 20 assessed) and two with familial FTD (from three assessed) who carried the mutation. The mutation was not carried by the three Native Americans or 360 patients from Asia or the Pacific Islands with sporadic ALS who were tested, or by 41 Asian patients with sporadic FTD. All patients with the repeat expansion had (partly or fully) the founder haplotype, suggesting a one-off expansion occurring about 1500 years ago. The pathogenic expansion was non-penetrant in individuals younger than 35 years, 50% penetrant by 58 years, and almost fully penetrant by 80 years. A common Mendelian genetic lesion in C9orf72 is implicated in many cases of sporadic and familial ALS and FTD. Testing for this pathogenic expansion should be considered in the management and genetic counselling of patients with these fatal neurodegenerative diseases. Full funding sources listed at end of paper (see Acknowledgments).
  The Lancet Neurology 03/2012; 11(4):323-30. · 23.46 Impact Factor
• Article: A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD.

  Alan E Renton, Elisa Majounie, Adrian Waite, Javier Simón-Sánchez, Sara Rollinson, J Raphael Gibbs, Jennifer C Schymick, Hannu Laaksovirta, John C van Swieten, Liisa Myllykangas, [......], Amalia Dutra, Evgenia Pak, John Hardy, Andrew Singleton, Nigel M Williams, Peter Heutink, Stuart Pickering-Brown, Huw R Morris, Pentti J Tienari, Bryan J Traynor
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  ABSTRACT: 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.
  Neuron 09/2011; 72(2):257-68. · 14.74 Impact Factor
• Article: Chromosome 9 ALS and FTD locus is probably derived from a single founder.

  Kin Mok, Bryan J Traynor, Jennifer Schymick, Pentti J Tienari, Hannu Laaksovirta, Terhi Peuralinna, Liisa Myllykangas, Adriano Chiò, Aleksey Shatunov, Bradley F Boeve, [......], Gabriele Mora, Karen E Morrison, Pamela J Shaw, Pamela Sara Rollinson, Ammar Al-Chalabi, Rosa Rademakers, Stuart Pickering-Brown, Richard W Orrell, Michael A Nalls, John Hardy
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  ABSTRACT: 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.
  Neurobiology of aging 09/2011; 33(1):209.e3-8. · 5.94 Impact Factor
• Article: Chromosome 9p21 in amyotrophic lateral sclerosis in Finland: a genome-wide association study.

  Hannu Laaksovirta, Terhi Peuralinna, Jennifer C Schymick, Sonja W Scholz, Shaoi-Lin Lai, Liisa Myllykangas, Raimo Sulkava, Lilja Jansson, Dena G Hernandez, J Raphael Gibbs, Michael A Nalls, David Heckerman, Pentti J Tienari, Bryan J Traynor
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  ABSTRACT: The genetic cause of amyotrophic lateral sclerosis (ALS) is not well understood. Finland is a well suited location for a genome-wide association study of ALS because the incidence of the disease is one of the highest in the world, and because the genetic homogeneity of the Finnish population enhances the ability to detect risk loci. We aimed to identify genetic risk factors for ALS in the Finnish population. We did a genome-wide association study of Finnish patients with ALS and control individuals by use of Illumina genome-wide genotyping arrays. DNA was collected from patients who attended an ALS specialty clinic that receives referrals from neurologists throughout Finland. Control samples were from a population-based study of elderly Finnish individuals. Patients known to carry D90A alleles of the SOD1 gene (n=40) were included in the final analysis as positive controls to assess whether our genome-wide association study was able to detect an association signal at this locus. We obtained samples from 442 patients with ALS and 521 control individuals. After quality control filters were applied, 318 167 single nucleotide polymorphisms (SNPs) from 405 people with ALS and 497 control individuals were available for analysis. We identified two association peaks that exceeded genome-wide significance. One was located on chromosome 21q22 (rs13048019, p=2·58×10(-8)), which corresponds to the autosomal recessive D90A allele of the SOD1 gene. The other was detected in a 232 kb block of linkage disequilibrium (rs3849942, p=9·11×10(-11)) in a region of chromosome 9p that was previously identified in linkage studies of families with ALS. Within this region, we defined a 42-SNP haplotype that was associated with significantly increased risk of ALS (p=7·47×10(-33) when people with familial ALS were compared with controls, odds ratio 21·0, 95% CI 11·2-39·1) and which overlapped with an association locus recently reported for frontotemporal dementia. For the 93 patients with familial ALS, the population attributable risk for the chromosome 9p21 locus was 37·9% (95% CI 27·7-48·1) and that for D90A homozygosity was 25·5% (16·9-34·1). The chromosome 9p21 locus is a major cause of familial ALS in the Finnish population. Our data suggest the presence of a founder mutation for chromosome 9p21-linked ALS. Furthermore, the overlap with the risk haplotype recently reported for frontotemporal dementia provides further evidence of a shared genetic cause for these two neurodegenerative diseases. National Institutes of Health and National Institute on Aging, Microsoft Research, ALS Association, Helsinki University Central Hospital, Finnish Academy, Finnish Medical Society Duodecim, and Kuopio University.
  The Lancet Neurology 10/2010; 9(10):978-85. · 23.46 Impact Factor
• Article: Magnetoencephalographic evidence of abnormal auditory processing in amyotrophic lateral sclerosis with bulbar signs.

  Eero Pekkonen, Daria Osipova, Hannu Laaksovirta
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  ABSTRACT: Amyotrophic lateral sclerosis (ALS) is characterized by progressive motor neuron damage that gives rise to muscle denervation. Besides motor neuron damage, conscious auditory processing appears to be impaired in ALS, whereas it has remained ambiguous whether preceding automatic auditory processing is abnormal in ALS and specifically in ALS with bulbar signs. Auditory evoked fields (AEFs) to monaurally presented frequent and infrequent tones with stimulus intervals of 500 and 2500 ms were recorded with magnetoencephalography (MEG) from 10 ALS patients having bulbar signs and from 10 age-matched healthy subjects. The amplitudes of the P50m and N100m responses, which index automatic auditory processing underlying stimulus detection, were significantly increased and P50m latency was shortened in ALS patients. MMNm, which reflects memory-based auditory comparison process, was increased in amplitude in the patient group, whereas the MMNm latency was similar in both groups. AEF latency and amplitude values failed to correlate with the severity of ALS as measured by ALS Functional Rating Scale (ALSFRS). The present results suggest that auditory processing underlying stimulus detection, and subsequent memory-based comparison processes are abnormal in ALS patients with severe bulbar signs. This might be due to cortical overactivity of excitatory neurotransmitter glutamate observed in ALS.
  Clinical Neurophysiology 03/2004; 115(2):309-15. · 3.41 Impact Factor