Lack of evidence for a genetic association between FGF20 and Parkinson's disease in Finnish and Greek patients

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

Genome-wide association study of neocortical Lewy-related pathology

Peer reviewe

Common genetic variation and susceptibility to partial epilepsies: a genome-wide association study

Partial epilepsies have a substantial heritability. However, the actual genetic causes are largely unknown. In contrast to many other common diseases for which genetic association-studies have successfully revealed common variants associated with disease risk, the role of common variation in partial epilepsies has not yet been explored in a well-powered study. We undertook a genome-wide association-study to identify common variants which influence risk for epilepsy shared amongst partial epilepsy syndromes, in 3445 patients and 6935 controls of European ancestry. We did not identify any genome-wide significant association. A few single nucleotide polymorphisms may warrant further investigation. We exclude common genetic variants with effect sizes above a modest 1.3 odds ratio for a single variant as contributors to genetic susceptibility shared across the partial epilepsies. We show that, at best, common genetic variation can only have a modest role in predisposition to the partial epilepsies when considered across syndromes in Europeans. The genetic architecture of the partial epilepsies is likely to be very complex, reflecting genotypic and phenotypic heterogeneity. Larger meta-analyses are required to identify variants of smaller effect sizes (odds ratio <1.3) or syndrome-specific variants. Further, our results suggest research efforts should also be directed towards identifying the multiple rare variants likely to account for at least part of the heritability of the partial epilepsies. Data emerging from genome-wide association-studies will be valuable during the next serious challenge of interpreting all the genetic variation emerging from whole-genome sequencing studie

Common genetic variation and susceptibility to partial epilepsies: a genome-wide association study

Partial epilepsies have a substantial heritability. However, the actual genetic causes are largely unknown. In contrast to many other common diseases for which genetic association-studies have successfully revealed common variants associated with disease risk, the role of common variation in partial epilepsies has not yet been explored in a well-powered study. We undertook a genome-wide association-study to identify common variants which influence risk for epilepsy shared amongst partial epilepsy syndromes, in 3445 patients and 6935 controls of European ancestry. We did not identify any genome-wide significant association. A few single nucleotide polymorphisms may warrant further investigation. We exclude common genetic variants with effect sizes above a modest 1.3 odds ratio for a single variant as contributors to genetic susceptibility shared across the partial epilepsies. We show that, at best, common genetic variation can only have a modest role in predisposition to the partial epilepsies when considered across syndromes in Europeans. The genetic architecture of the partial epilepsies is likely to be very complex, reflecting genotypic and phenotypic heterogeneity. Larger meta-analyses are required to identify variants of smaller effect sizes (odds ratio <1.3) or syndrome-specific variants. Further, our results suggest research efforts should also be directed towards identifying the multiple rare variants likely to account for at least part of the heritability of the partial epilepsies. Data emerging from genome-wide association-studies will be valuable during the next serious challenge of interpreting all the genetic variation emerging from whole-genome sequencing studies

Genetics of Neurodegeneration : Alzheimer, Lewy body and motor neuron diseases in the Finnish population

This thesis project aimed to study the genetic background of common neurodegenerative diseases such as Alzheimer's disease (AD), dementia with Lewy bodies (DLB) and amyotrophic lateral sclerosis (ALS) in the Finnish population. In the first study, we analysed the role of the amyloid precursor protein (APP) and apolipoprotein E (APOE) genes in AD neuropathology. Mutations in the APP gene cause early-onset familial AD and there is some evidence that APP gene variants would play a role in late-onset AD, too. We genotyped more than 50 common variations in the APP gene and sequenced the APP promoter area to detect rare variations in the area, both known and new. In the Finnish elderly population we did not find any of the APP variations to clearly associate with neuropathologically diagnosed AD or with any of the neuropathological features of AD such as cortical β-amyloid, cerebrovascular β-amyloid or neurofibrillary tangles. In addition, the APOEε4 results were updated, using the whole Vantaa85+ cohort. APOE ε4 is currently the strongest known risk factor for late-onset AD. We found a very strong association of APOE ε4 to all neuropathological features of AD. In the second study, we investigated how the common variants in the α-synuclein (SNCA) gene affect different brain pathologies. -synuclein is the main component of the Lewy bodies, which are the pathological hallmarks of PD and DLB, and which are sometimes found also in AD. We genotyped 11 SNPs from the SNCA gene region. We found no association with the cortical β-amyloid and only a faint one with Lewy related pathology. However, we found an association with neurofibrillary tangles. The SNP (rs2572324) associated with a p=0.004 after the Bonferroni correction. The two-locus analysis suggest an independent effect of APOE ε4 (OR=8.67) and rs2572324 (OR=3.36). In the subjects with both risk factors the effect was almost multiplicatively increased (OR=23.3). 35 subjects out of 38 with both risk factors had severe tau-pathology. These results demonstrated the first evidence for a role of genetic variation in SNCA in tau pathology. Moreover, β-amyloid pathology was not associated with the SNCA variants, demonstrating a dissection of genetic effect on the two principal pathological features of AD. In the third study, we performed a whole-genome genotyping using Finnish ALS samples. The Vantaa85+ study subjects were used as controls. This was the first ALS genome-wide association study to find a genome-wide significant association. The location associated with familial ALS was on the chromosome 9p21, which had been noticed before, but the area had been much larger. The area has also been associated with frontotemporal dementia (FTD). Now we managed to define the area with a 42 SNP haplotype. This considerably reduced the area of interest (down to 232 kb) and increased the possibility to find the mutation behind the disease. This haplotype was found in around 40% of the Finnish familial ALS cases and likely explains the high rate of ALS as well as FTD in Finnish population. In the fourth study, we performed a genome-wide association study of DLB in the Vantaa85+ cohort and found two novel areas to be associated with DLB: The c2p21 location with 9 SNP haplotype (p=5.2x10-7) and the c6p21 location with 6 SNP haplotype (p=1.3x10-7). The c6p21 was significant at the genome-wide level. The c2orf21 haplotype has two genes on its area, c2orf72 and SPTBN1. SPTBN1 is the candidate gene since it encodes beta-spectrin, a component of Lewy bodies, while c2orf72 is barely expressed in the brain. The c6p21 associated haplotype block is located in the HLA region and includes HLA-DPB1 and -DPA1 genes. These studies show that the Finnish population is well-suited to study the genetics of neurodegeneration. Our results showed that neuropathologically defined parameters and diagnoses are strongly associated with genetic risk factors, even with relatively low numbers of samples. Hence, phenotypic precision (pathology) is an important element of the statistical power of a study.Ikä on suurimpia riskitekijöitä erilaisten myöhäisiän hermosolujen rappeumasairauksien eli neurodegeneratiivisten tautien puhkeamiselle. Väestön vanheneminen lisää siis näiden sairauksien kuten Alzheimerin taudin (AT), Lewy-kappaletaudin ja aivojen amyloidiangiopatian esiintyvyyttä. Tässä vaitöskirjassa on tutkittu ja löydetty joukko neurodegeneraatioon vaikuttavia geneettisiä tekijöitä. Nämä antavat tietoa tautien syntymekanismeista ja niihin vaikuttavista tekijöistä. Tutkimuksissa käytetty Vantaa 85+ aineisto on hyvin ainutlaatuinen, sillä se sisältää kaikki vielä vuonna 1991 Vantaalla elossa olleet yli 85-vuotiaat henkilöt. Osalle heistä on myöhemmin voitu tehdä ruumiinavaus ja kattava aivojen patologinen tutkimus. Sen sijaan, että vertaisimme kliinisiä oireita, jotka voivat vaihdella potilaiden välillä paljonkin, diagnoosi on voitu varmistaa ja tutkia aivoissa tapahtuneiden biokemiallisten muutosten ja geenien variaatioiden yhteyttä. Aivoista on karakterisoitu ja kvantifioitu AT:iin liittyviä muutoksia, kuten aivokuoren ja aivoverisuonten beta-amyloidi kertymät, tau-proteiinin muodostamat neurofibrillivyyhdet sekä Lewy-kappale taudissa aivokuorella tavattavat alfa-synucleiinin kertymät. Apolipoproteiini E:n (APOE) muoto ε4 on vahvin riskitekijä myöhäisiän AT:ssa. Myös Vantaa 85+ aineistossa APOE4 assosioituu hyvin vahvasti AT:n aiheuttamiin patologisiin muutoksiin. Amyloidi-beta peptidi on AT:n amyloidiplakeissa tapahtuvien proteiinikertymien keskeisin ainesosa. Amyloidi-beta peptidi pilkotaan amyloidiprekursoriproteiinista (APP). Emme voineet todeta APP-geenin yleisillä variaatioilla olevan vaikutusta myöhäisiän AT:hen. Erityishuomiota saivat myös α-synukleiinigeenin yleiset variaatiot. α-synukleiini on Lewy-kappaleiden keskeinen ainesosa. Lewy-kappaleita muodostuu hermosoluihin erityisesti Parkinsonin taudissa ja Lewy-kappaletaudissa. Ehkä hieman yllättäen emme löytäneet merkittävää yhteyttä Lewy-kappaleiden esiintyvyyden ja α-synukleiini geenin variaatioiden välillä. Sen sijaan yksi variaatio assosioitui merkittävästi tau-proteiinin kertymiin. Tau-proteiini on toinen AT:ssa kertyvä proteiini, joka muodostaa solujen sisäisiä vyyhtejä. Aikaisemmin on todettu α -synukleiini- ja tau -proteiinien välistä vuorovaikutusta, mutta tämä on ensimmäinen kerta kun tällaista havaitaan geneettisella tasolla. Löytö kertoo AT:n ja Lewy-kappaletaudin läheisestä suhteesta. Etsimme myös Lewy-kappaletautiin vaikuttavia perintötekijöitä suorittamalla koko genomin kattavan assosiaatioanalyysin. Analysoiduista genomeista löytyi kaksi aluetta, joiden variaatiot voitiin yhdistää tautiin. Yksi sijaitsee β-spectrin-nimisen geenin alueella. β-spectrin proteiinin tiedetään olevan vuorovaikutuksessa α-synukleiinin kanssa. Toinen variaatio taas sijaitsee HLA alueella. HLA alue on osa ihmisen immuniteettia ja vahvistaa osaltaan käsitystä kehon puolustusjärjestelmän tärkeydestä neurodegeneratiivisissa taudeissa. ALS (amyotrooppinen lateraalinen skleroosi) on liikehermoja tuhoava tauti ja yleisempi Suomessa kuin muualla Euroopassa. Teimme koko genomin kattavan analyysin Suomesta kerätyistä ALS näytteista ja vertasimme niitä Vantaa 85+ aineistoon. Löysimme perinnölliseen ALS:iin assosioituvan alueen kromosomista 9p21. Alue on aiemminkin kytketty tautiin, mutta rajasimme sen nyt huomattavasti pienemmäksi, eli vain kahden geenin kattavaksi. Tältä alueelta sittemmin löydetty C9ORF72 geenin mutaatio näyttää selittävän yli 40% suomalaisista perinnöllisistä ALS tapauksista ja osaltaan selittävän Suomen korkeaa ALS ilmaantuuvuutta. Kyseinen mutaatio on kytketty myös frontotemporaaliseen dementiaan. Tauti on yleisempi Suomessa kuin muualla Euroopassa ja mainittu mutaatio mahdollisesti myös selittää tämän ilmiön

Alzheimer risk loci and associated neuropathology in a population-based study (Vantaa 85+)

Peer reviewe

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

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