Molecular genetics of primary open angle glaucoma and exfoliation syndrome

Glaucoma is the second leading cause of blindness worldwide. It is a group of optic neuropathies, characterized by progressive optic nerve degeneration, excavation of the optic disc due to apoptosis of retinal ganglion cells and corresponding visual field defects. Open angle glaucoma (OAG) is a subtype of glaucoma, classified according to the age of onset into juvenile and adult- forms with a cut-off point of 40 years of age. The prevalence of OAG is 1-2% of the population over 40 years and increases with age. During the last decade several candidate loci and three candidate genes, myocilin (MYOC), optineurin (OPTN) and WD40-repeat 36 (WDR36), for OAG have been identified. Exfoliation syndrome (XFS), age, elevated intraocular pressure and genetic predisposition are known risk factors for OAG. XFS is characterized by accumulation of grayish scales of fibrillogranular extracellular material in the anterior segment of the eye. XFS is overall the most common identifiable cause of glaucoma (exfoliation glaucoma, XFG). In the past year, three single nucleotide polymorphisms (SNPs) on the lysyl oxidase like 1 (LOXL1) gene have been associated with XFS and XFG in several populations. This thesis describes the first molecular genetic studies of OAG and XFS/XFG in the Finnish population. The role of the MYOC and OPTN genes and fourteen candidate loci was investigated in eight Finnish glaucoma families. Both candidate genes and loci were excluded in families, further confirming the heterogeneous nature of OAG. To investigate the genetic basis of glaucoma in a large Finnish family with juvenile and adult onset OAG, we analysed the MYOC gene in family members. Glaucoma associated mutation (Thr377Met) was identified in the MYOC gene segregating with the disease in the family. This finding has great significance for the family and encourages investigating the MYOC gene also in other Finnish OAG families. In order to identify the genetic susceptibility loci for XFS, we carried out a genome-wide scan in the extended Finnish XFS family. This scan produced promising candidate locus on chromosomal region 18q12.1-21.33 and several additional putative susceptibility loci for XFS. This locus on chromosome 18 provides a solid starting point for the fine-scale mapping studies, which are needed to identify variants conferring susceptibility to XFS in the region. A case-control and family-based association study and family-based linkage study was performed to evaluate whether SNPs in the LOXL1 gene contain a risk for XFS, XFG or POAG in the Finnish patients. A significant association between the LOXL1 gene SNPs and XFS and XFG was confirmed in the Finnish population. However, no association was detected with POAG. Probably also other genetic and environmental factors are involved in the pathogenesis of XFS and XFG.Glaukooma on maailmanlaajuisesti toiseksi yleisin sokeuden aiheuttaja. Se on ryhmä näköhermon eteneviä sairauksia, jossa näköhermon rappeutuminen johtaa näkökenttäpuutoksiin. Avokulmaglaukooma (OAG) on glaukoomaperheentautien alatyyppi, joka luokitellaan puhkeamisiän mukaan aikuistyypin (>40 vuotta) ja nuoruustyypin OAG:iin. Suomessa OAG:n esiintyvyys yli 70-vuotiailla on noin 5.4 %. Molekyyligeneettisissä tutkimuksissa on tunnistettu useita OAG:in alttiusgeenialueita ja kolme alttiusgeeniä, myocilin (MYOC), optineurin (OPTN) ja WD40-repeat 36 (WDR36). Glaukooman kiistattomia riskitekijöitä ovat eksfoliaatio-oireyhtymä, kohonnut silmänpaine, ikä ja perintötekijät. Eksfoliaatio-oireyhtymässä (XFS) todetaan eksfoliaatiota eli hilsetystä silmän etuosan rakenteissa. XFS on yleisin tunnistettavissa oleva syy glaukoomalle (eksfoliaatioglaukooma, XFG). Viime vuoden aikana on osoitettu vahva assosiaatio kolmen lysyl oxidase like 1 (LOXL1) geenin variantin sekä XFS ja XFG:n välillä useissa väestöissä. Tämän väitöskirjatyön tarkoituksena oli tunnistaa OAG ja XFS/XFG:lle altistavia geneettisiä tekijöitä geenien kartoitus- ja sekvensointimenetelmien avulla. Tutkimukset ovat ensimmäisiä OAG ja XFS/XFG alttiusgeenejä kartoittavia tutkimuksia Suomessa. Väitöskirjatyössä selvitettiin alttiusgeenien MYOC ja OPTN ja 14 alttiusgeenialueen osallisuutta glaukoomassa kahdeksassa suomalaisessa glaukoomasuvussa. Sekä alttiusgeenit että alttiusgeenialueet pystyttiin sulkemaan pois glaukooman taustalta perheistä, mikä osaltaan vahvisti OAG:n olevan taustaltaan heterogeeninen. Tutkimuksessa tunnistettiin glaukoomalle altistava mutaatio (Thr377Met) MYOC geenissä, suuressa suvussa, jossa esiintyi sekä nuoruus- että aikuistyypin OAG:ia. Löydös kannustaa MYOC geenin tutkimista myös muissa suomalaisissa glaukoomasuvuissa. Väitöskirjatyössä pyrittiin tunnistamaan perimästä XFS:lle altistavia geneettisiä tekijöitä perimänlaajuisen kartoitustutkimuksen avulla suuressa suomalaisessa XFS suvussa. Lupaavin alttiusgeenialue paikannettiin kromosomiin 18q12.1-21.33, mutta myös useat muut perimän alueet antoivat viitteitä kytkennästä XFS:aan. Tämä alttiusgeenialue alue tarjoaa oivan perustan jatkotutkimuksille, joissa pyritään tunnistamaan alueelta XFS:n syntyyn yhteydessä olevia geneettisiä variantteja. Väitöskirjassa osoitettiin LOXL1 geenin variaatioiden assosioituvat vahvasti XFS ja XFG:aan myös suomalaisilla potilailla ja riskialleelien frekvenssien olevan samaa tasoa kuin muissa kaukasialaisissa populaatioissa. On kuitenkin todennäköistä että tulevaisuudessa tullaan tunnistamaan myös muita XFS ja XFG:n syntyyn yhteydessä olevia geneettisiä variantteja

Uusia menetelmiä järven kunnostushankkeen suunnitteluun

Ympäristöhallinnossa on pitkään kehitetty erilaisia menetelmiä ja työkaluja vesienhoidon ja -suojelun ja vesistöjen kunnostuksen suunnitteluprosessien tueksi, mm. erilaisia osallistavan suunnittelun menetelmiä, tietojärjestelmiä sekä luonnon prosesseja ja toimenpiteiden vaikutuksia kuvaavia malleja ja arviointityökaluja. Tässä julkaisussa esitetään Vesienhoidon kustannustehokkaat menetelmät ja monitavoitteiset toimintatavat (VeKuMe) -hankkeessa kehitetty järven kunnostuksen yleissuunnitteluprosessi, johon on yhdistetty eräitä edellä mainittuja ympäristöhallinnossa kehitettyjä ja kehitteillä olevia menetelmiä ja malleja vesistön kuormituksen ja nykytilan arviointiin, toimenpiteiden tunnistamiseen, vaikutusten ja kustannusten arviointiin sekä toimenpidevaihtoehtojen hyötyjen arviointiin. Työssä on pohdittu, mitä vaiheita hyvässä, järven vesiensuojelu- ja kunnostushankkeen suunnitteluprosessissa pitäisi olla ja mitä tehtäviä eri vaiheisiin sisältyy. Samalla on mietitty, minkälaisille suunnittelun apuvälineille olisi tarvetta eri suunnittelutehtävissä, mitä käyttökelpoisia apuvälineitä on jo olemassa ja miten niitä voitaisiin suunnitteluprosessissa tehokkaasti hyödyntää. Työn tuloksena syntyneessä suunnitteluprosessissa on otettu huomioon, että on tärkeää tunnistaa järvessä esiintyvien ongelmien syyt ja niiden seuraukset ja arvioida monipuolisesti vesiensuojelu- ja kunnostustoimenpiteiden vaikutuksia, toteutettavuutta, kustannustehokkuutta ja hyötyjä. Suunnitteluprosessi pyrkii sovittamaan yhteen erilaiset tarpeet ja tavoitteet, jotta suunnitelma saisi laajasti hyväksyntää eri sidosryhmiltä. Tämä julkaisu on tarkoitettu pääasiassa suunnitteluprosesseja vetävien asiantuntijatahojen käyttöön. Kohderyhminä ovat lähinnä ELY-keskusten ja kuntien asiantuntijat ja kunnostussuunnitelmia laativat konsultit sekä kunnostushankkeita rahoittavat ja toteuttavat organisaatiot. Julkaisua voidaan hyödyntää myös eri alojen oppilaitoksissa

Association of the MYOC p.(Gln368Ter) Variant With Glaucoma in a Finnish Population

IMPORTANCE The c.1102C>T, p.(Gln368Ter) variant in themyocilin (MYOC) gene is a known risk allele for glaucoma. It is the most common MYOC risk variant for glaucoma among individuals of European ancestry, and its prevalence is highest in Finland. Furthermore, exfoliation syndrome has high prevalence in Scandinavia, making the Finnish population ideal to study the association of the variant with different types of glaucoma. OBJECTIVES To examine the association and penetrance of MYOC p.(Gln368Ter) (rs74315329) variant with different types of glaucoma in a Finnish population. DESIGN, SETTING, AND PARTICIPANTS This genetic association study included individuals of Finnish ancestry in the FinnGen project. The participants were collected from Finnish biobanks, and the disease end points were defined using nationwide registries. The MYOC c.1102C>T variant was either directly genotyped or imputed with microarrays. Recruitment of samples to FinnGen was initiated in 2017, and data analysis was performed between December 2019 and May 2020. MAIN OUTCOMES AND MEASURES The main outcomes were odds ratios (ORs) and penetrance with different types of glaucoma and in different age groups. RESULTS A total of 218 792 individuals were included in this study (mean [SD] age 52.4 [17.5] years; 123 579 women [56.5%]), including 8591 (3.9%) with glaucoma, 3412 (1.6%) with primary open-angle glaucoma, 1515 (0.7%) with exfoliation glaucoma, 892 (0.4%) with normal-tension glaucoma, and 4766 (2.2%) with suspected glaucoma. The minor allele frequency of MYOC p.(Gln368Ter) was 0.28%. Individuals with the heterozygous variant had higher odds of primary open-angle glaucoma (OR, 3.36; 95% CI, 2.55-4.37), overall glaucoma (OR, 2.58; 95% CI, 2.12-3.13), suspected glaucoma (OR, 2.53; 95% CI, 1.93-3.26), exfoliation glaucoma (OR, 2.61; 95% CI, 1.60-4.02), and undergoing glaucoma-related operations (OR, 5.45; 95% CI, 2.95-9.28). The penetrance of heterozygous MYOC p.(Gln368Ter) was 5.2% in individuals with primary open-angle glaucoma, 9.6% in individuals with glaucoma, 5.4% in individuals with suspected glaucoma, and 1.9% in individuals with exfoliation glaucoma. There was no significant association with normal-tension glaucoma (OR, 1.69; 95% CI, 0.72-3.35). CONCLUSIONS AND RELEVANCE This genetic association study found that the MYOC p.(Gln368Ter) variant was associated with exfoliation glaucoma. The association with normal-tension glaucoma could not be replicated. These findings suggest that MYOC p.(Gln368Ter) was associated with open-angle glaucoma and exfoliation glaucoma in a Finnish population.Peer reviewe

Rare protein-altering variants in ANGPTL7 lower intraocular pressure and protect against glaucoma

Protein-altering variants that are protective against human disease provide in vivo validation of therapeutic targets. Here we use genotyping data from UK Biobank (n = 337,151 unrelated White British individuals) and FinnGen (n = 176,899) to conduct a search for protein-altering variants conferring lower intraocular pressure (IOP) and protection against glaucoma. Through rare protein-altering variant association analysis, we find a missense variant in ANGPTL7 in UK Biobank (rs28991009, p.Gln175His, MAF = 0.8%, genotyped in 82,253 individuals with measured IOP and an independent set of 4,238 glaucoma patients and 250,660 controls) that significantly lowers IOP (beta = -0.53 and -0.67 mmHg for heterozygotes, -3.40 and -2.37 mmHg for homozygotes, P = 5.96 x 10(-9) and 1.07 x 10(-13) for corneal compensated and Goldman-correlated IOP, respectively) and is associated with 34% reduced risk of glaucoma (P = 0.0062). In FinnGen, we identify an ANGPTL7 missense variant at a greater than 50-fold increased frequency in Finland compared with other populations (rs147660927, p.Arg220Cys, MAF Finland = 4.3%), which was genotyped in 6,537 glaucoma patients and 170,362 controls and is associated with a 29% lower glaucoma risk (P = 1.9 x 10(-12) for all glaucoma types and also protection against its subtypes including exfoliation, primary open-angle, and primary angle-closure). We further find three rarer variants in UK Biobank, including a protein-truncating variant, which confer a strong composite lowering of IOP (P = 0.0012 and 0.24 for Goldman-correlated and corneal compensated IOP, respectively), suggesting the protective mechanism likely resides in the loss of interaction or function. Our results support inhibition or down-regulation of ANGPTL7 as a therapeutic strategy for glaucoma. Author summary Glaucoma is a common eye disease that damages the optic nerve. Using intraocular pressure, which is a known modifiable risk factor and predictive measure for glaucoma, genome-wide association studies have identified dozens of genetic variants likely affecting disease risk. However, the identification of potential therapeutic targets from those discoveries has been challenging because the functional consequences and the causal variants of the suggested common variant associations are typically unclear. Here, we present a strategy to scan for rare protein-altering variants, which provides direct insights into the functional consequence and the therapeutic effects, using more than 514,000 individuals with European ancestries in two population cohorts in the UK and Finland. We discover an allelic series of multiple rare ANGPTL7 missense and nonsense variants in UK Biobank that lower intraocular pressure and reduces the risk of glaucoma. We further identify an ANGPTL7 missense variant in FinnGen cohort with more than 50-fold enrichment in the Finnish population that provides protection against glaucoma and its subtypes. Our results highlight the benefits of multi-cohort analysis for the discovery of rare protein-altering variants in common diseases and indicate ANGPTL7 as a therapeutic target for glaucoma.Peer reviewe

Integrated analyses of growth differentiation factor-15 concentration and cardiometabolic diseases in humans

Growth differentiation factor-15 (GDF15) is a stress response cytokine that is elevated in several cardiometabolic diseases and has attracted interest as a potential therapeutic target. To further explore the association of GDF15 with human disease, we conducted a broad study into the phenotypic and genetic correlates of GDF15 concentration in up to 14,099 individuals. Assessment of 772 traits across 6610 participants in FINRISK identified associations of GDF15 concentration with a range of phenotypes including all-cause mortality, cardiometabolic disease, respiratory diseases and psychiatric disorders, as well as inflammatory markers. A meta-analysis of genome-wide association studies (GWAS) of GDF15 concentration across three different assay platforms (n=14,099) confirmed significant heterogeneity due to a common missense variant (rs1058587; p.H202D) in GDF15, potentially due to epitope-binding artefacts. After conditioning on rs1058587, statistical fine mapping identified four independent putative causal signals at the locus. Mendelian randomisation (MR) analysis found evidence of a causal relationship between GDF15 concentration and high-density lipoprotein (HDL) but not body mass index (BMI). Using reverse MR, we identified a potential causal association of BMI on GDF15 (IVW p(FDR) = 0.0040). Taken together, our data derived from human population cohorts do not support a role for moderately elevated GDF15 concentrations as a causal factor in human cardiometabolic disease but support its role as a biomarker of metabolic stress.Peer reviewe

Rare protein-altering variants in ANGPTL7 lower intraocular pressure and protect against glaucoma

Protein-altering variants that are protective against human disease provide in vivo validation of therapeutic targets. Here we use genotyping data from UK Biobank (n = 337,151 unrelated White British individuals) and FinnGen (n = 176,899) to conduct a search for protein-altering variants conferring lower intraocular pressure (IOP) and protection against glaucoma. Through rare protein-altering variant association analysis, we find a missense variant in ANGPTL7 in UK Biobank (rs28991009, p.Gln175His, MAF = 0.8%, genotyped in 82,253 individuals with measured IOP and an independent set of 4,238 glaucoma patients and 250,660 controls) that significantly lowers IOP (beta = -0.53 and -0.67 mmHg for heterozygotes, -3.40 and -2.37 mmHg for homozygotes, P = 5.96 x 10-9 and 1.07 x 10-13 for corneal compensated and Goldman-correlated IOP, respectively) and is associated with 34% reduced risk of glaucoma (P = 0.0062). In FinnGen, we identify an ANGPTL7 missense variant at a greater than 50-fold increased frequency in Finland compared with other populations (rs147660927, p.Arg220Cys, MAF Finland = 4.3%), which was genotyped in 6,537 glaucoma patients and 170,362 controls and is associated with a 29% lower glaucoma risk (P = 1.9 x 10-12 for all glaucoma types and also protection against its subtypes including exfoliation, primary open-angle, and primary angle-closure). We further find three rarer variants in UK Biobank, including a protein-truncating variant, which confer a strong composite lowering of IOP (P = 0.0012 and 0.24 for Goldman-correlated and corneal compensated IOP, respectively), suggesting the protective mechanism likely resides in the loss of interaction or function. Our results support inhibition or down-regulation of ANGPTL7 as a therapeutic strategy for glaucoma.Author summaryGlaucoma is a common eye disease that damages the optic nerve. Using intraocular pressure, which is a known modifiable risk factor and predictive measure for glaucoma, genome-wide association studies have identified dozens of genetic variants likely affecting disease risk. However, the identification of potential therapeutic targets from those discoveries has been challenging because the functional consequences and the causal variants of the suggested common variant associations are typically unclear. Here, we present a strategy to scan for rare protein-altering variants, which provides direct insights into the functional consequence and the therapeutic effects, using more than 514,000 individuals with European ancestries in two population cohorts in the UK and Finland. We discover an allelic series of multiple rare ANGPTL7 missense and nonsense variants in UK Biobank that lower intraocular pressure and reduces the risk of glaucoma. We further identify an ANGPTL7 missense variant in FinnGen cohort with more than 50-fold enrichment in the Finnish population that provides protection against glaucoma and its subtypes. Our results highlight the benefits of multi-cohort analysis for the discovery of rare protein-altering variants in common diseases and indicate ANGPTL7 as a therapeutic target for glaucoma.</div

Genome-Wide Meta-Analysis of Sciatica in Finnish Population

Sciatica or the sciatic syndrome is a common and often disabling low back disorder in the working-age population. It has a relatively high heritability but poorly understood molecular mechanisms. The Finnish population is a genetic isolate where small founder population and bottleneck events have led to enrichment of certain rare and low frequency variants. We performed here the first genome-wide association (GWAS) and meta-analysis of sciatica. The meta-analysis was conducted across two GWAS covering 291 Finnish sciatica cases and 3671 controls genotyped and imputed at 7.7 million autosomal variants. The most promising loci (pPeer reviewe

The phenotypic and molecular spectrum of PEHO syndrome and PEHO-like disorders

Stepwise regression. The regression coefficients along with their 95 % CIs, and the bootstrap inclusion frequencies of infependent variables for the models selected using automatic stepwise selection algorithm (backward elimination and forward selection) with AIC, BIC and the Likelihood ratio test (p = 0.05). (PDF 229 kb

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele