Browsing by Subject "SNP"

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  • Calboli, Federico C. F.; Byström, Pär; Merilä, Juha (2016)
    Specialization for the use of different resources can lead to ecological speciation. Accordingly, there are numerous examples of ecologically specialized pairs of fish species in postglacial lakes. Using a polymorphic panel of single nucleotide variants, we tested for genetic footprints of within-lake population stratification in nine-spined sticklebacks (Pungitius pungitius) collected from three habitats (viz. littoral, benthic, and pelagic) within a northern Swedish lake. Analyses of admixture, population structure, and relatedness all supported the conclusion that the fish from this lake form a single interbreeding unit.
  • Japan Scoliosis Clinical Res Grp; Texas Scottish Rite Hosp Children (2018)
    Adolescent idiopathic scoliosis (AIS) is a common spinal deformity with the prevalence of approximately 3%. We previously conducted a genome-wide association study (GWAS) using a Japanese cohort and identified a novel locus on chromosome 9p22.2. However, a replication study using multi-population cohorts has not been conducted. To confirm the association of 9p22.2 locus with AIS in multi-ethnic populations, we conducted international meta-analysis using eight cohorts. In total, we analyzed 8,756 cases and 27,822 controls. The analysis showed a convincing evidence of association between rs3904778 and AIS. Seven out of eight cohorts had significant P value, and remaining one cohort also had the same trend as the seven. The combined P was 3.28 x 10(-18) (odds ratio = 1.19, 95% confidence interval = 1.14-1.24). In silico analyses suggested that BNC2 is the AIS susceptibility gene in this locus.
  • Int League Against Epilepsy Consor; Stevelink, Remi; Pangilinan, Faith; Jansen, Floor E.; Eriksson, Johan G.; Kälviäinen, Reetta; Kantanen, Anne-Mari; Lehesjoki, Anna-Elina; Palotie, Aarno (2019)
    Altered vitamin B6 metabolism due to pathogenic variants in the gene PNPO causes early onset epileptic encephalopathy, which can be treated with high doses of vitamin B6. We recently reported that single nucleotide polymorphisms (SNPs) that influence PNPO expression in the brain are associated with genetic generalized epilepsy (GGE). However, it is not known whether any of these GGE-associated SNPs influence vitamin B6 metabolite levels. Such an influence would suggest that vitamin B6 could play a role in GGE therapy. Here, we performed genome-wide association studies (GWAS) to assess the influence of GGE associated genetic variants on measures of vitamin B6 metabolism in blood plasma in 2232 healthy individuals. We also asked if SNPs that influence vitamin B6 were associated with GGE in 3122 affected individuals and 20,244 controls. Our GWAS of vitamin B6 metabolites reproduced a previous association and found a novel genome-wide significant locus. The SNPs in these loci were not associated with GGE. We found that 84 GGE-associated SNPs influence expression levels of PNPO in the brain as well as in blood. However, these SNPs were not associated with vitamin B6 metabolism in plasma. By leveraging polygenic risk scoring (PRS), we found suggestive evidence of higher catabolism and lower levels of the active and transport forms of vitamin B6 in GGE, although these findings require further replication.
  • Mace, Aurelien; Tuke, Marcus A.; Deelen, Patrick; Kristiansson, Kati; Mattsson, Hannele; Noukas, Margit; Sapkota, Yadav; Schick, Ursula; Porcu, Eleonora; Rueger, Sina; McDaid, Aaron F.; Porteous, David; Winkler, Thomas W.; Salvi, Erika; Shrine, Nick; Liu, Xueping; Ang, Wei Q.; Zhang, Weihua; Feitosa, Mary F.; Venturini, Cristina; van der Most, Peter J.; Rosengren, Anders; Wood, Andrew R.; Beaumont, Robin N.; Jones, Samuel E.; Ruth, Katherine S.; Yaghootkar, Hanieh; Tyrrell, Jessica; Havulinna, Aki S.; Boers, Harmen; Magi, Reedik; Kriebel, Jennifer; Mueller-Nurasyid, Martina; Perola, Markus; Nieminen, Markku; Lokki, Marja-Liisa; Kahonen, Mika; Viikari, Jorma S.; Geller, Frank; Lahti, Jari; Palotie, Aarno; Koponen, Paivikki; Lundqvist, Annamari; Rissanen, Harri; Bottinger, Erwin P.; Afaq, Saima; Wojczynski, Mary K.; Lenzini, Petra; Nolte, Ilja M.; Sparso, Thomas; Schupf, Nicole; Christensen, Kaare; Perls, Thomas T.; Newman, Anne B.; Werge, Thomas; Snieder, Harold; Spector, Timothy D.; Chambers, John C.; Koskinen, Seppo; Melbye, Mads; Raitakari, Olli T.; Lehtimaki, Terho; Tobin, Martin D.; Wain, Louise V.; Sinisalo, Juha; Peters, Annette; Meitinger, Thomas; Martin, Nicholas G.; Wray, Naomi R.; Montgomery, Grant W.; Medland, Sarah E.; Swertz, Morris A.; Vartiainen, Erkki; Borodulin, Katja; Mannisto, Satu; Murray, Anna; Bochud, Murielle; Jacquemont, Sebastien; Rivadeneira, Fernando; Hansen, Thomas F.; Oldehinkel, Albertine J.; Mangino, Massimo; Province, Michael A.; Deloukas, Panos; Kooner, Jaspal S.; Freathy, Rachel M.; Pennell, Craig; Feenstra, Bjarke; Strachan, David P.; Lettre, Guillaume; Hirschhorn, Joel; Cusi, Daniele; Heid, Iris M.; Hayward, Caroline; Mannik, Katrin; Beckmann, Jacques S.; Loos, Ruth J. F.; Nyholt, Dale R.; Metspalu, Andres; Eriksson, Johan G.; Weedon, Michael N.; Salomaa, Veikko; Franke, Lude; Reymond, Alexandre; Frayling, Timothy M.; Kutalik, Zoltan (2017)
    There are few examples of robust associations between rare copy number variants (CNVs) and complex continuous human traits. Here we present a large-scale CNV association meta-analysis on anthropometric traits in up to 191,161 adult samples from 26 cohorts. The study reveals five CNV associations at 1q21.1, 3q29, 7q11.23, 11p14.2, and 18q21.32 and confirms two known loci at 16p11.2 and 22q11.21, implicating at least one anthropometric trait. The discovered CNVs are recurrent and rare (0.01-0.2%), with large effects on height (> 2.4 cm), weight ( 5 kg), and body mass index (BMI) (> 3.5 kg/m(2)). Burden analysis shows a 0.41 cm decrease in height, a 0.003 increase in waist-to-hip ratio and increase in BMI by 0.14 kg/m2 for each Mb of total deletion burden (P = 2.5 x 10(-10), 6.0 x 10(-5), and 2.9 x 10(-3)). Our study provides evidence that the same genes (e.g., MC4R, FIBIN, and FMO5) harbor both common and rare variants affecting body size and that anthropometric traits share genetic loci with developmental and psychiatric disorders.
  • Rastas, Pasi; Calboli, Federico C. F.; Guo, Baocheng; Shikano, Takahito; Merilä, Juha (2016)
    High-density linkage maps are important tools for genome biology and evolutionary genetics by quantifying the extent of recombination, linkage disequilibrium, and chromosomal rearrangements across chromosomes, sexes, and populations. They provide one of the best ways to validate and refine de novo genome assemblies, with the power to identity errors in assemblies increasing with marker density. However, assembly of high-density linkage maps is still challenging due to software limitations. We describe Lep-MAP2, a software for ultradense genome-wide linkage map construction. Lep-MAP2 can handle various family structures and can account for achiasmatic meiosis to gain linkage map accuracy. Simulations show that Lep-MAP2 outperforms other available mapping software both in computational efficiency and accuracy. When applied to two large F-2-generation recombinant crosses between two nine-spined stickleback (Pungitius pungitius) populations, it produced two high-density (similar to 6 markers/cM) linkage maps containing 18,691 and 20,054 single nucleotide polymorphisms. The two maps showed a high degree of synteny, but female maps were 1.5-2 times longer than male maps in all linkage groups, suggesting genome-wide recombination suppression in males. Comparison with the genome sequence of the three-spined stickleback (Gasterosteus aculeatus) revealed a high degree of interspecific synteny with a low frequency (
  • Koskela, Outi (Helsingfors universitet, 2012)
    Pharmacogenetics is the study of variations in DNA sequence as related to drug response, i.e. pharmacokinetics, drug efficacy and adverse effects. The literature review of the thesis covers pharmacogenetics of analgesics. The most studied genetic variations affecting the analgesics response are the 118A>G variant of µ-opioid receptor gene (OPRM1) and several variations in the genes coding for cytochrome (CYP) P450 enzymes. Also variations in the COMT gene and the ABCB1 gene coding for P-glycoprotein have been shown to modify the response to analgesics. Genetic polymorphism of CYP2D6, CYP3A4 and CYP3A5 enzymes was studied in the experimental part of the thesis. The aim of the study was to determine if the allele and haplotype frequencies of the CYP2D6, CYP3A4 and CYP3A5 gene variations are different between Finnish breast cancer patients and healthy volunteers. The results will be further used to explore whether the genetic polymorphism of these metabolic enzymes affects the response to a certain drug substance. The study population consisted of 996 Finnish breast cancer patients. Common genetic variants affecting the enzymatic activity of CYP2D6, CYP3A4 and CYP3A5 were studied. In addition to gene copy number, ten single nucleotide polymorphisms (SNP) of the CYP2D6 gene were genotyped. For CYP3A4 gene, genotyping was done for intron 6 SNP rs35599367 shown to decrease CYP3A4 gene expression. CYP3A5 SNP 6986A>G leading to splicing defect and premature STOP codon was also genotyped. Genotyping and copy number determination was done using PCR-based TaqMan® 5'-nuclease method. CYP2D6 haplotype analysis and phenotype predictions were derived based on genotype data. According to CYP2D6 enzyme activity individuals are commonly classified as poor metabolizers (PM), intermediate metabolizers (IM), extensive metabolizers (EM) or ultra-rapid metabolizers (UM). The frequencies of CYP2D6 phenotypic classes in our study population were the following: PM, 2.8%; IM 2.0 %; EM 87.7% and UM 7.6%. The haplotype and phenotype frequencies determined for breast cancer patients coincide with the values observed earlier for Finnish healthy volunteers. In our study population, the minor allele frequency (MAF) of the CYP3A4 rs35599367 SNP was 2.7% and the MAF of the CYP3A5 6986G>A SNP 7.6%. The MAF of CYP3A5 6986G>A SNP found in our study is in line with the previous findings for Finnish healthy volunteers. There are no previous publications on the frequency of CYP3A4 rs35599367 SNP in Finnish population. In conclusion, no differences were detected in the frequency of the studied CYP2D6 and CYP3A5 genetic variations between Finnish breast cancer patients and healthy volunteers. Frequency of CYP3A4 rs35599367 SNP in Finnish healthy volunteers should be determined in order to compare it with our findings in the population comprising of breast cancer patients. The results of this study can be further used to explore the effects of CYP2D6, CYP3A4 and CYP3A5 genetic polymorphism on drug response.
  • Savilammi, Tiina; Papakostas, Spiros; Leder, Erica H.; Vollestad, L. Asbjorn; Debes, Paul V.; Primmer, Craig R. (2021)
    Temperature is a key environmental parameter affecting both the phenotypes and distributions of organisms, particularly ectotherms. Rapid organismal responses to thermal environmental changes have been described for several ectotherms; however, the underlying molecular mechanisms often remain unclear. Here, we studied whole genome cytosine methylation patterns of European grayling (Thymallus thymallus) embryos from five populations with contemporary adaptations of early life history traits at either 'colder' or 'warmer' spawning grounds. We reared fish embryos in a common garden experiment using two temperatures that resembled the 'colder' and 'warmer' conditions of the natal natural environments. Genome-wide methylation patterns were similar in populations originating from colder thermal origin subpopulations, whereas single nucleotide polymorphisms uncovered from the same data identified strong population structure among isolated populations, but limited structure among interconnected populations. This was surprising because the previously studied gene expression response among populations was mostly plastic, and mainly influenced by the developmental temperature. These findings support the hypothesis of the magnified role of epigenetic mechanisms in modulating plasticity. The abundance of consistently changing methylation loci between two warmer-to-colder thermal origin population pairs suggests that local adaptation has shaped the observed methylation patterns. The dynamic nature of the methylomes was further highlighted by genome-wide and site-specific plastic responses. Our findings support both the presence of a plastic response in a subset of CpG loci, and the evolutionary role of methylation divergence between populations adapting to contrasting thermal environments.
  • Fang, Bohao; Merilä, Juha; Matschiner, Michael; Momigliano, Paolo (2020)
    Incomplete lineage sorting (ILS) can lead to biased divergence time estimates. To explore if and how ILS has influenced the results of a recent study of worldwide phylogeny of three-spined sticklebacks (Gasterosteus aculeatus), we estimated divergence times among major clades by applying both a concatenation approach and the multispecies coalescent (MSC) model to single-nucleotide polymorphisms. To further test the influence of different calibration strategies, we applied different calibrations to the root and to younger nodes in addition to the ones used in the previous study. Both the updated calibrations and the application of the MSC model influenced divergence time estimates, sometimes significantly. The new divergence time estimates were more ancient than in the previous study for older nodes, whereas the estimates of younger nodes were not strongly affected by the re-analyses. However, given the applied MSC method employs a simple substitution model and cannot account for changes in population size, we suggest that different analytical approaches and calibration strategies should be used in order to explore uncertainty in divergence time estimates. This study provides a valuable reference timeline for the ages of worldwide three-spined stickleback populations and emphasizes the need to embrace, rather than obscure, uncertainties around divergence time estimates.
  • Martikainen, K.; Tyrisevä, A. M.; Matilainen, K.; Pösö, J.; Uimari, P. (2017)
    Single nucleotide polymorphism (SNP) data enable the estimation of inbreeding at the genome level. In this study, we estimated inbreeding levels for 19,075 Finnish Ayrshire cows genotyped with a low-density SNP panel (8K). The genotypes were imputed to 50K density, and after quality control, 39,144 SNPs remained for the analysis. Inbreeding coefficients were estimated for each animal based on the percentage of homozygous SNPs (F-PH), runs of homozygosity (F-ROH) and pedigree (F-PED). Phenotypic records were available for 13,712 animals including non-return rate (NRR), number of inseminations (AIS) and interval from first to last insemination (IFL) for heifers and up to three parities for cows, as well as interval from calving to first insemination (ICF) for cows. Average F-PED was 0.02, F-ROH 0.06 and F-PH 0.63. A correlation of 0.71 was found between F-PED and F-ROH, 0.66 between F-PED and F-PH and 0.94 between F-ROH and F-PH. Pedigree-based inbreeding coefficients did not show inbreeding depression in any of the traits. However, when F-ROH or F-PH was used as a covariate, significant inbreeding depression was observed; a 10% increase in F-ROH was associated with 5days longer IFL0 and IFL1, 2weeks longer IFL3 and 3days longer ICF2 compared to non-inbred cows.
  • Ahlström, Sirkku; Bergman, Paula; Jokela, Ritva; Ottensmann, Linda; Ahola-Olli, Ari; Pirinen, Matti; Olkkola, Klaus T.; Kaunisto, Mari A.; Kalso, Eija (2021)
    Background: Rocuronium, a common neuromuscular blocking agent, is mainly excreted unchanged in urine (10-25%) and bile ( 70%). Age, sex, liver blood flow, smoking, medical conditions, and ethnic background can affect its pharmacological actions. However, reasons for the wide variation in rocuronium requirements are mostly unknown. We hypothesised that pharmacogenetic factors might explain part of the variation. Methods: One thousand women undergoing surgery for breast cancer were studied. Anaesthesia was maintained with propofol (50-100 mg kg(-1) min(-1)) and remifentanil (0.05-0.25 mg kg(-1) min(-1)). Neuromuscular block was maintained with rocuronium to keep the train-of-four ratio at 0-10%. DNA was extracted from peripheral blood and genotyped with a next-generation genotyping array. The genome-wide association study (GWAS) was conducted using an additive linear regression model with PLINK software. The FINEMAP tool and data from the Genotype-Tissue Expression project v8 were utilised to study the locus further. Results: The final patient population comprised 918 individuals. Of the clinical variables tested, age, BMI, ASA physical status, and total dose of propofol correlated significantly (all P Conclusions: Genetic variation in the gene SLCO1A2, encoding OATP1A2, an uptake transporter, accounted for 4% of the variability in rocuronium consumption. The underlying mechanism remains unknown.
  • De Keyzer, Els L. R.; De Corte, Zoe; Van Steenberge, Maarten; Raeymaekers, Joost A. M.; Calboli, Federico C. F.; Kmentova, Nikol; Mulimbwa, Theophile N'Sibula; Virgilio, Massimiliano; Vangestel, Carl; Mulungula, Pascal Masilya; Volckaert, Filip A. M.; Vanhove, Maarten P. M. (2019)
    BackgroundClupeid fisheries in Lake Tanganyika (East Africa) provide food for millions of people in one of the world's poorest regions. Due to climate change and overfishing, the clupeid stocks of Lake Tanganyika are declining. We investigate the population structure of the Lake Tanganyika sprat Stolothrissa tanganicae, using for the first time a genomic approach on this species. This is an important step towards knowing if the species should be managed separately or as a single stock. Population structure is important for fisheries management, yet understudied for many African freshwater species. We hypothesize that distinct stocks of S. tanganicae could be present due to the large size of the lake (isolation by distance), limnological variation (adaptive evolution), or past separation of the lake (historical subdivision). On the other hand, high mobility of the species and lack of obvious migration barriers might have resulted in a homogenous population.ResultsWe performed a population genetic study on wild-caught S. tanganicae through a combination of mitochondrial genotyping (96 individuals) and RAD sequencing (83 individuals). Samples were collected at five locations along a north-south axis of Lake Tanganyika. The mtDNA data had low global FST and, visualised in a haplotype network, did not show phylogeographic structure. RAD sequencing yielded a panel of 3504 SNPs, with low genetic differentiation (F-ST=0.0054; 95% CI: 0.0046-0.0066). PCoA, fineRADstructure and global F-ST suggest a near-panmictic population. Two distinct groups are apparent in these analyses (F-ST=0.1338 95% CI: 0.1239,0.1445), which do not correspond to sampling locations. Autocorrelation analysis showed a slight increase in genetic difference with increasing distance. No outlier loci were detected in the RADseq data.ConclusionOur results show at most very weak geographical structuring of the stock and do not provide evidence for genetic adaptation to historical or environmental differences over a north-south axis. Based on these results, we advise to manage the stock as one population, integrating one management strategy over the four riparian countries. These results are a first comprehensive study on the population structure of these important fisheries target species, and can guide fisheries management.
  • De Keyzer, Els L R; De Corte, Zoë; Van Steenberge, Maarten; Raeymaekers, Joost A M; Calboli, Federico C F; Kmentová, Nikol; N’Sibula Mulimbwa, Théophile; Virgilio, Massimiliano; Vangestel, Carl; Mulungula, Pascal M; Volckaert, Filip A M; Vanhove, Maarten P M (BioMed Central, 2019)
    Abstract Background Clupeid fisheries in Lake Tanganyika (East Africa) provide food for millions of people in one of the world’s poorest regions. Due to climate change and overfishing, the clupeid stocks of Lake Tanganyika are declining. We investigate the population structure of the Lake Tanganyika sprat Stolothrissa tanganicae, using for the first time a genomic approach on this species. This is an important step towards knowing if the species should be managed separately or as a single stock. Population structure is important for fisheries management, yet understudied for many African freshwater species. We hypothesize that distinct stocks of S. tanganicae could be present due to the large size of the lake (isolation by distance), limnological variation (adaptive evolution), or past separation of the lake (historical subdivision). On the other hand, high mobility of the species and lack of obvious migration barriers might have resulted in a homogenous population. Results We performed a population genetic study on wild-caught S. tanganicae through a combination of mitochondrial genotyping (96 individuals) and RAD sequencing (83 individuals). Samples were collected at five locations along a north-south axis of Lake Tanganyika. The mtDNA data had low global FST and, visualised in a haplotype network, did not show phylogeographic structure. RAD sequencing yielded a panel of 3504 SNPs, with low genetic differentiation (FST = 0.0054; 95% CI: 0.0046–0.0066). PCoA, fineRADstructure and global FST suggest a near-panmictic population. Two distinct groups are apparent in these analyses (FST = 0.1338 95% CI: 0.1239,0.1445), which do not correspond to sampling locations. Autocorrelation analysis showed a slight increase in genetic difference with increasing distance. No outlier loci were detected in the RADseq data. Conclusion Our results show at most very weak geographical structuring of the stock and do not provide evidence for genetic adaptation to historical or environmental differences over a north-south axis. Based on these results, we advise to manage the stock as one population, integrating one management strategy over the four riparian countries. These results are a first comprehensive study on the population structure of these important fisheries target species, and can guide fisheries management.
  • Kambur, Oleg; Kaunisto, Mari A.; Winsvold, Bendik S.; Wilsgaard, Tom; Stubhaug, Audun; Zwart, John A.; Kalso, Eija; Nielsen, Christopher S. (2018)
    P2X7 is a nonselective cation channel activated by extracellular ATP. P2X7 activation contributes to the proinflammatory response to injury or bacterial invasion and mediates apoptosis. Recently, P2X7 function has been linked to chronic inflammatory and neuropathic pain. P2X7 may contribute to pain modulation both by effects on peripheral tissue injury underlying clinical pain states, and through alterations in central nervous system processing, as suggested by animal models. To further test its role in pain sensitivity, we examined whether variation within the P2RX7 gene, which encodes the P2X7 receptor, was associated with experimentally induced pain in human patients. Experimental pain was assessed in Tromso 6, a longitudinal and cross-sectional population-based study (N = 3016), and the BrePainGen cohort, consisting of patients who underwent breast cancer surgery (N = 831). For both cohorts, experimental pain intensity and tolerance were assessed with the cold-pressor test. In addition, multisite chronic pain was assessed in Tromso 6 and pain intensity 1 week after surgery was assessed in BrePainGen. We tested whether the single-nucleotide polymorphism rs7958311, previously implicated in clinical pain, was associated with experimental and clinical pain phenotypes. In addition, we examined effects of single-nucleotide polymorphisms rs208294 and rs208296, for which previous results have been equivocal. Rs7958311 was associated with experimental pain intensity in the meta-analysis of both cohorts. Significant associations were also found for multisite pain and postoperative pain. Our results strengthen the existing evidence and suggest that P2X7 and genetic variation in the P2RX7-gene may be involved in the modulation of human pain sensitivity.
  • Revez, Joana; Llarena, Ann-Katrin; Schott, Thomas; Kuusi, Markku; Hakkinen, Marjaana; Kivistö, Rauni; Hänninen, Marja-Liisa; Rossi, Mirko (2014)
  • Kudinov, Andrei A; Dementieva, Natalia V; Mitrofanova, Olga V; Stanishevskaya, Olga I; Fedorova, Elena S; Larkina, Tatiana A; Mishina, Arina I; Plemyashov, Kirill V; Griffin, Darren K; Romanov, Michael N (BioMed Central, 2019)
    Abstract Background The Russian White is a gene pool breed, registered in 1953 after crossing White Leghorns with local populations and, for 50 years, selected for cold tolerance and high egg production (EL). The breed has great potential in meeting demands of local food producers, commercial farmers and biotechnology sector of specific pathogen-free (SPF) eggs, the former valuing the breed for its egg weight (EW), EL, age at first egg (AFE), body weight (BW), and the latter for its yield of extraembryonic fluid (YEF) in 12.5-day embryos, ratio of extraembryonic fluid to egg weight, and embryo mass. Moreover, its cold tolerance has been presumably associated with day-old chick down colour (DOCDC) – white rather than yellow, the genetic basis of these traits being however poorly understood. Results We undertook genome-wide association studies (GWASs) for eight performance traits using single nucleotide polymorphism (SNP) genotyping of 146 birds and an Illumina 60KBeadChip. Several suggestive associations (p < 5.16*10− 5) were found for YEF, AFE, BW and EW. Moreover, on chromosome 2, an association with the white DOCDC was found where there is an linkage disequilibrium block of SNPs including genes that are responsible not for colour, but for immune resistance. Conclusions The obtained GWAS data can be used to explore the genetics of immunity and carry out selection for increasing YEF for SPF eggs production.
  • Kudinov, Andrei A.; Dementieva, Natalia V.; Mitrofanova, Olga V.; Stanishevskaya, Olga I.; Fedorova, Elena S.; Larkina, Tatiana A.; Mishina, Arina I.; Plemyashov, Kirill V.; Griffin, Darren K.; Romanov, Michael N. (2019)
    Background: The Russian White is a gene pool breed, registered in 1953 after crossing White Leghorns with local populations and, for 50 years, selected for cold tolerance and high egg production (EL). The breed has great potential in meeting demands of local food producers, commercial farmers and biotechnology sector of specific pathogen-free (SPF) eggs, the former valuing the breed for its egg weight (EW), EL, age at first egg (AFE), body weight (BW), and the latter for its yield of extraembryonic fluid (YEF) in 12.5-day embryos, ratio of extraembryonic fluid to egg weight, and embryo mass. Moreover, its cold tolerance has been presumably associated with day-old chick down colour (DOCDC) white rather than yellow, the genetic basis of these traits being however poorly understood. Results: We undertook genome-wide association studies (GWASs) for eight performance traits using single nucleotide polymorphism (SNP) genotyping of 146 birds and an Illumina 60KBeadChip. Several suggestive associations (p <5.16*10(-5)) were found for YEF, AFE, BW and EW. Moreover, on chromosome 2, an association with the white DOCDC was found where there is an linkage disequilibrium block of SNPs including genes that are responsible not for colour, but for immune resistance. Conclusions: The obtained GWAS data can be used to explore the genetics of immunity and carry out selection for increasing YEF for SPF eggs production.
  • Anstee, Quentin M.; Darlay, Rebecca; Cockell, Simon; Meroni, Marica; Govaere, Olivier; Tiniakos, Dina; Burt, Alastair D.; Bedossa, Pierre; Palmer, Jeremy; Liu, Yang-Lin; Aithal, Guruprasad P.; Allison, Michael; Yki-Järvinen, Hannele; Vacca, Michele; Dufour, Jean-Francois; Invernizzi, Pietro; Prati, Daniele; Ekstedt, Mattias; Kechagias, Stergios; Francque, Sven; Petta, Salvatore; Bugianesi, Elisabetta; Clement, Karine; Ratziu, Vlad; Schattenberg, Jörn M.; Valenti, Luca; Day, Christopher P.; Cordell, Heather J.; Daly, Ann K. (2020)
    Background and Aims Genetic factors associated with non-alcoholic fatty liver disease (NAFLD) remain incompletely understood. To date, most GWAS studies have adopted radiologically assessed hepatic triglyceride content as reference phenotype and so cannot address steatohepatitis or fibrosis. We describe a genome-wide association study (GWAS) encompassing the full spectrum of histologically characterized NAFLD. Methods The GWAS involved 1483 European NAFLD cases and 17781 genetically-matched population controls. A replication cohort of 559 NAFLD cases and 945 controls was genotyped to confirm signals showing genome-wide or close to genome-wide significance. Results Case-control analysis identified signals showing p-values ≤ 5 x 10-8 at four locations (chromosome (chr) 2 GCKR/C2ORF16; chr4 HSD17B13; chr19 TM6SF2; chr22 PNPLA3) together with two other signals with p
  • Koskinen, Lotta L. E.; Seppälä, Eija H.; Belanger, Janelle M.; Arumilli, Meharji; Hakosalo, Osmo; Jokinen, Paivi; Nevalainen, Elisa M.; Viitmaa, Ranno; Jokinen, Tarja S.; Oberbauer, Anita M.; Lohi, Hannes (2015)
    Background: Idiopathic epilepsy is a common neurological disease in human and domestic dogs but relatively few risk genes have been identified to date. The seizure characteristics, including focal and generalised seizures, are similar between the two species, with gene discovery facilitated by the reduced genetic heterogeneity of purebred dogs. We have recently identified a risk locus for idiopathic epilepsy in the Belgian Shepherd breed on a 4.4 megabase region on CFA37. Results: We have expanded a previous study replicating the association with a combined analysis of 157 cases and 179 controls in three additional breeds: Schipperke, Finnish Spitz and Beagle (p(c) = 2.9e-07, p(GWAS) = 1.74E-02). A targeted resequencing of the 4.4 megabase region in twelve Belgian Shepherd cases and twelve controls with opposite haplotypes identified 37 case-specific variants within the ADAM23 gene. Twenty-seven variants were validated in 285 cases and 355 controls from four breeds, resulting in a strong replication of the ADAM23 locus (p(raw) = 2.76e-15) and the identification of a common 28 kb-risk haplotype in all four breeds. Risk haplotype was present in frequencies of 0.49-0.7 in the breeds, suggesting that ADAM23 is a low penetrance risk gene for canine epilepsy. Conclusions: These results implicate ADAM23 in common canine idiopathic epilepsy, although the causative variant remains yet to be identified. ADAM23 plays a role in synaptic transmission and interacts with known epilepsy genes, LGI1 and LGI2, and should be considered as a candidate gene for human epilepsies.
  • Ollila, Hanna M.; Kronholm, Erkki; Kettunen, Johannes; Silander, Kaisa; Perola, Markus; Porkka-Heiskanen, Tarja; Salomaa, Veikko; Paunio, Tiina (2016)