Browsing by Subject "VARIANTS"

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  • Atrial Fibrillation Genetics Conso; Int Stroke Genetics Consortium; Pulit, Sara L.; Lyytikäinen, Leo-Pekka; Seppälä, Ilkka; Malik, Rainer; Sinisalo, Juha; Vlachopoulou, Efthymia; Lokki, Marja-Liisa; Tatlisumak, Turgut; Happola, Olli (2018)
    Objective We sought to assess whether genetic risk factors for atrial fibrillation (AF) can explain cardioembolic stroke risk. Methods We evaluated genetic correlations between a previous genetic study of AF and AF in the presence of cardioembolic stroke using genome-wide genotypes from the Stroke Genetics Network (N = 3,190 AF cases, 3,000 cardioembolic stroke cases, and 28,026 referents). We tested whether a previously validated AF polygenic risk score (PRS) associated with cardioembolic and other stroke subtypes after accounting for AF clinical risk factors. Results We observed a strong correlation between previously reported genetic risk for AF, AF in the presence of stroke, and cardioembolic stroke (Pearson r = 0.77 and 0.76, respectively, across SNPs with p <4.4 x 10(-4) in the previous AF meta-analysis). An AF PRS, adjusted for clinical AF risk factors, was associated with cardioembolic stroke (odds ratio [OR] per SD = 1.40, p = 1.45 x 10(-48)), explaining similar to 20% of the heritable component of cardioembolic stroke risk. The AF PRS was also associated with stroke of undetermined cause (OR per SD = 1.07,p = 0.004), but no other primary stroke subtypes (all p > 0.1). Conclusions Genetic risk of AF is associated with cardioembolic stroke, independent of clinical risk factors. Studies are warranted to determine whether AF genetic risk can serve as a biomarker for strokes caused by AF.
  • Luo, Guo; Ambati, Aditya; Lin, Ling; Bonvalet, Melodie; Partinen, Markku; Ji, Xuhuai; Maecker, Holden Terry; Mignot, Emmanuel Jean-Marie (2018)
    Type 1 narcolepsy (T1N) is caused by hypocretin/orexin (HCRT) neuronal loss. Association with the HLA DQB1*06:02/DQA1*01:02 (98% vs. 25%) heterodimer (DQ0602), T cell receptors (TCR) and other immune loci suggest autoimmunity but autoantigens are unknown. Onset is seasonal and associated with influenza A, notably pandemic 2009 H1N1 (pH1N1) infection and vaccination (Pandemrix). Peptides derived from HCRT and influenza A, including pH1N1, were screened for DQ0602 binding and presence of cognate DQ0602 tetramer-peptide-specific CD4(+) T cells tested in 35 T1N cases and 22 DQ0602 controls. Higher reactivity to influenza pHA(273-287) (pH1N1 specific), PR8 (H1N1 pre-2009 and H2N2)-specific NP17-31 and C-amidated but not native version of HCRT54-66 and HCRT86-97 (HCRTNH2) were observed in T1N. Single-cell TCR sequencing revealed sharing of CDR3 beta TRBV4-2-CASSQETQGRNYGYTF in HCRTNH2 and pHA(273-287)-tetramers, suggesting molecular mimicry. This public CDR3 beta uses TRBV4-2, a segment modulated by T1N-associated SNP rs1008599, suggesting causality. TCR-alpha/beta CDR3 motifs of HCRT54-66-NH2 and HCRT86-97-NH2 tetramers were extensively shared: notably public CDR3 alpha, TRAV2-CAVETDSWGKLQF-TRAJ24, that uses TRAJ24, a chain modulated by T1N-associated SNPs rs1154155 and rs1483979. TCR-alpha/beta CDR3 sequences found in pHA(273-287), NP17-31, and HCRTNH2 tetramer-positive CD4(+) cells were also retrieved in single INF-gamma-secreting CD4(+) sorted cells stimulated with Pandemrix, independently confirming these results. Our results provide evidence for autoimmunity and molecular mimicry with flu antigens modulated by genetic components in the pathophysiology of T1N.
  • Turunen, Joni A.; Markkinen, Salla; Wilska, Rosi; Saarinen, Silva; Raivio, Virpi; Tall, Martin; Lehesjoki, Anna-Elina; Kivela, Tero T. (2016)
    Purpose: Germline mutations of the BRCA1-associated protein-1 gene (BAP1) predispose carriers to uveal melanoma. We report the population-based frequency of germline pathogenic variants of BAP1 in Finnish patients with uveal melanoma who live in a high-risk region for this cancer. Design: Cohort study. Participants: In Finland, uveal melanomas are treated centrally in the Ocular Oncology Service, Helsinki University Hospital. We collected clinical data and genomic DNA from 148 of 188 consecutive patients diagnosed from January 2010 through December 2012. Seven of these patients from 6 families had a history of uveal melanoma in 1 relative, and 2 patients from 2 additional families had such a history in 2 relatives. Methods: Sequencing BAP1. Main Outcome Measures: Pathogenic variants in BAP1. Results: We found 2 different pathogenic variants in BAP1 in 3 patients. Two patients had a single nucleotide insertion in exon 14 resulting in a shift of reading frame. Both had a family history of uveal melanoma in at least 1 relative. One patient without a family history of uveal melanoma had a single nucleotide substitution in the conserved splice donor site of intron 2. BAP1 cancer predisposition syndrome-related cancers were present in all 3 families. The overall frequency of BAP1 pathogenic variants was 2.0% (3/148; 95% confidence interval, 0.4-5.8), the frequency among patients 50 years of age or younger was 3.6% (1/28; 95% confidence interval, 0.1-18), and a pathogenic variant was detected in 2 of 8 families with a history of uveal melanoma. Conclusions: The frequency of BAP1 germline pathogenic variants in consecutive Finnish patients with uveal melanoma who come from a high-risk region for the development of this cancer is comparable with reports from other populations. (C) 2016 by the American Academy of Ophthalmology.
  • Kirchhoff, Tomas; Gaudet, Mia M.; Antoniou, Antonis C.; McGuffog, Lesley; Humphreys, Manjeet K.; Dunning, Alison M.; Bojesen, Stig E.; Nordestgaard, Borge G.; Flyger, Henrik; Kang, Daehee; Yoo, Keun-Young; Noh, Dong-Young; Ahn, Sei-Hyun; Dork, Thilo; Schuermann, Peter; Karstens, Johann H.; Hillemanns, Peter; Couch, Fergus J.; Olson, Janet; Vachon, Celine; Wang, Xianshu; Cox, Angela; Brock, Ian; Elliott, Graeme; Reed, Malcolm W. R.; Burwinkel, Barbara; Meindl, Alfons; Brauch, Hiltrud; Hamann, Ute; Ko, Yon-Dschun; Broeks, Annegien; Schmidt, Marjanka K.; Van 't Veer, Laura J.; Braaf, Linde M.; Johnson, Nichola; Fletcher, Olivia; Gibson, Lorna; Peto, Julian; Turnbull, Clare; Seal, Sheila; Renwick, Anthony; Rahman, Nazneen; Wu, Pei-Ei; Yu, Jyh-Cherng; Hsiung, Chia-Ni; Shen, Chen-Yang; Southey, Melissa C.; Hopper, John L.; Nevanlinna, Heli; Heikkinen, Tuomas; EMBRACE, BCAC-CIMBA, HEBON, AOCS Study Grp, kConFab, GENICA Network, SWE-BRCA (2012)
  • Zheng, Guoqiao; Catalano, Calogerina; Bandapalli, Obul Reddy; Paramasivam, Nagarajan; Chattopadhyay, Subhayan; Schlesner, Matthias; Sijmons, Rolf; Hemminki, Akseli; Dymerska, Dagmara; Lubinski, Jan; Hemminki, Kari; Försti, Asta (2020)
    Simple Summary Familial clustering of cancer and identification of high- and low-risk cancer predisposition gene variants implicate that there are families that are at a high to moderate excess risk of cancer. We wanted to test genetically whether there are families protected from cancer. We whole-genome sequenced 51 elderly individuals without any personal or family history of cancer. We identified less high-risk loss-of-function variants in known and suggested cancer predisposition genes in these cancer-free individuals than in the general population. However, our results for low-risk variants were not conclusive. Our study suggests that random environmental causes of cancer are so dominant that a clear demarcation of cancer-free populations using genetic data may not be feasible. However, carrier identification of and counseling about prevalent high-risk cancer predisposition genes is useful. Familial clustering, twin concordance, and identification of high- and low-penetrance cancer predisposition variants support the idea that there are families that are at a high to moderate excess risk of cancer. To what extent there may be families that are protected from cancer is unknown. We wanted to test genetically whether cancer-free families share fewer breast, colorectal, and prostate cancer risk alleles than the population at large. We addressed this question by whole-genome sequencing (WGS) of 51 elderly cancer-free individuals whose numerous (ca. 1000) family members were found to be cancer-free ('cancer-free families', CFFs) based on face-to-face interviews. The average coverage of the 51 samples in the WGS was 42x. We compared cancer risk allele frequencies in cancer-free individuals with those in the general population available in public databases. The CFF members had fewer loss-of-function variants in suggested cancer predisposition genes compared to the ExAC data, and for high-risk cancer predisposition genes, no pathogenic variants were found in CFFs. For common low-penetrance breast, colorectal, and prostate cancer risk alleles, the results were not conclusive. The results suggest that, in line with twin and family studies, random environmental causes are so dominant that a clear demarcation of cancer-free populations using genetic data may not be feasible.
  • Jarvis, Kirsten Brunsvig; LeBlanc, Marissa; Tulstrup, Morten; Nielsen, Rikke Linnemann; Albertsen, Birgitte Klug; Gupta, Ramneek; Huttunen, Pasi; Jonsson, Olafur Gisli; Rank, Cecilie Utke; Ranta, Susanna; Ruud, Ellen; Saks, Kadri; Trakymiene, Sonata Saulyte; Tuckuviene, Ruta; Schmiegelow, Kjeld (2019)
    Introduction: Thromboembolism is a serious toxicity of acute lymphoblastic leukemia treatment, and contributes to substantial morbidity and mortality. Several single nucleotide polymorphisms have been associated with thromboembolism in the general population; however, their impact in patients with acute lymphoblastic leukemia, particularly in children, remains uncertain. Materials and methods: We collected constitutional DNA and prospectively registered thromboembolic events in 1252 patients, 1-45 years, with acute lymphoblastic leukemia included in the Nordic Society of Pediatric Hematology and Oncology ALL2008 protocol in the Nordic and Baltic countries (7/2008-7/2016). Based on previously published data and a priori power calculations, we selected four single nucleotide polymorphisms: F5 rs6025, F11 rs2036914, FGG rs2066865, and ABO rs8176719. Results: The 2.5 year cumulative incidence of thromboembolism was 7.1% (95% confidence interval (CI) 5.6-8.5). F11 rs2036914 was associated with thromboembolism (hazard ratio (HR) 1.52, 95%CI 1.11-2.07) and there was a borderline significant association for FGG rs2066865 (HR 1.37, 95%CI 0.99-1.91), but no association for ABO rs8176719 or F5 rs6025 in multiple cox regression. A genetic risk score based on F11 rs2036914 and FGG rs2066865 was associated with thromboembolism (HR 1.45 per risk allele, 95%CI 1.15-1.81), the association was strongest in adolescents 10.0-17.9 years (HR 1.64). Conclusion: If validated, a F11 rs2036914/FGG rs2066865 risk prediction model should be tested as a stratification tool for prevention of thromboembolism in patients with acute lymphoblastic leukemia.
  • Westra, Harm-Jan; Arends, Danny; Esko, Tonu; Peters, Marjolein J.; Schurmann, Claudia; Schramm, Katharina; Kettunen, Johannes; Yaghootkar, Hanieh; Fairfax, Benjamin P.; Andiappan, Anand Kumar; Li, Yang; Fu, Jingyuan; Karjalainen, Juha; Platteel, Mathieu; Visschedijk, Marijn; Weersma, Rinse K.; Kasela, Silva; Milani, Lili; Tserel, Liina; Peterson, Part; Reinmaa, Eva; Hofman, Albert; Uitterlinden, Andre G.; Rivadeneira, Fernando; Homuth, Georg; Petersmann, Astrid; Lorbeer, Roberto; Prokisch, Holger; Meitinger, Thomas; Herder, Christian; Roden, Michael; Grallert, Harald; Ripatti, Samuli; Perola, Markus; Wood, Andrew R.; Melzer, David; Ferrucci, Luigi; Singleton, Andrew B.; Hernandez, Dena G.; Knight, Julian C.; Melchiotti, Rossella; Lee, Bernett; Poidinger, Michael; Zolezzi, Francesca; Larbi, Anis; Wang, De Yun; van den Berg, Leonard H.; Veldink, Jan H.; Rotzschke, Olaf; Makino, Seiko; Salomaa, Veikko; Strauch, Konstantin; Voelker, Uwe; van Meurs, Joyce B. J.; Metspalu, Andres; Wijmenga, Cisca; Jansen, Ritsert C.; Franke, Lude (2015)
    The functional consequences of trait associated SNPs are often investigated using expression quantitative trait locus (eQTL) mapping. While trait-associated variants may operate in a cell-type specific manner, eQTL datasets for such cell-types may not always be available. We performed a genome-environment interaction (GxE) meta-analysis on data from 5,683 samples to infer the cell type specificity of whole blood cis-eQTLs. We demonstrate that this method is able to predict neutrophil and lymphocyte specific cis-eQTLs and replicate these predictions in independent cell-type specific datasets. Finally, we show that SNPs associated with Crohn's disease preferentially affect gene expression within neutrophils, including the archetypal NOD2 locus.
  • Einarsdottir, Elisabet; Grauers, Anna; Wang, Jingwen; Jiao, Hong; Escher, Stefan A.; Danielsson, Aina; Simony, Ane; Andersen, Mikkel; Christensen, Steen Bach; Åkesson, Kristina; Kou, Ikuyo; Khanshour, Anas M.; Ohlin, Acke; Wise, Carol; Ikegawa, Shiro; Kere, Juha; Gerdhem, Paul (2017)
    A Swedish pedigree with an autosomal dominant inheritance of idiopathic scoliosis was initially studied by genetic linkage analysis, prioritising genomic regions for further analysis. This revealed a locus on chromosome 1 with a putative risk haplotype shared by all affected individuals. Two affected individuals were subsequently exome-sequenced, identifying a rare, non-synonymous variant in the CELSR2 gene. This variant is rs141489111, a c. G6859A change in exon 21 (NM_001408), leading to a predicted p. V2287I (NP_001399.1) change. This variant was found in all affected members of the pedigree, but showed reduced penetrance. Analysis of tagging variants in CELSR1-3 in a set of 1739 Swedish-Danish scoliosis cases and 1812 controls revealed significant association (p = 0.0001) to rs2281894, a common synonymous variant in CELSR2. This association was not replicated in case-control cohorts from Japan and the US. No association was found to variants in CELSR1 or CELSR3. Our findings suggest a rare variant in CELSR2 as causative for idiopathic scoliosis in a family with dominant segregation and further highlight common variation in CELSR2 in general susceptibility to idiopathic scoliosis in the Swedish-Danish population. Both variants are located in the highly conserved GAIN protein domain, which is necessary for the auto-proteolysis of CELSR2, suggesting its functional importance.
  • Tukiainen, Taru; Pirinen, Matti; Sarin, Antti-Pekka; Ladenvall, Claes; Kettunen, Johannes; Lehtimaeki, Terho; Lokki, Marja-Liisa; Perola, Markus; Sinisalo, Juha; Vlachopoulou, Efthymia; Eriksson, Johan G.; Groop, Leif; Jula, Antti; Jaervelin, Marjo-Riitta; Raitakari, Olli T.; Salomaa, Veikko; Ripatti, Samuli (2014)
  • Lawrenson, Kate; Li, Qiyan; Kar, Siddhartha; Seo, Ji-Heui; Tyrer, Jonathan; Spindler, Tassja J.; Lee, Janet; Chen, Yibu; Karst, Alison; Drapkin, Ronny; Aben, Katja K. H.; Anton-Culver, Hoda; Antonenkova, Natalia; Baker, Helen; Bandera, Elisa V.; Bean, Yukie; Beckmann, Matthias W.; Berchuck, Andrew; Bisogna, Maria; Bjorge, Line; Bogdanova, Natalia; Brinton, Louise A.; Brooks-Wilson, Angela; Bruinsma, Fiona; Butzow, Ralf; Campbell, Ian G.; Carty, Karen; Chang-Claude, Jenny; Chenevix-Trench, Georgia; Chen, Anne; Chen, Zhihua; Cook, Linda S.; Cramer, Daniel W.; Cunningham, Julie M.; Cybulski, Cezary; Dansonka-Mieszkowska, Agnieszka; Dennis, Joe; Dicks, Ed; Doherty, Jennifer A.; Doerk, Thilo; Du Bois, Andreas; Duerst, Matthias; Eccles, Diana; Easton, Douglas T.; Edwards, Robert P.; Eilber, Ursula; Ekici, Arif B.; Leminen, Arto; Nevanlinna, Heli; Pelttari, Liisa M.; Australian Ovarian Canc Study Grp (2015)
    Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions associated with HGSOC risk (P
  • Schwarz, N.; Bast, T.; Gaily, E.; Golla, G.; Gorman, K. M.; Griffiths, L. R.; Hahn, A.; Hukin, J.; King, M.; Korff, C.; Miranda, M. J.; Moller, R. S.; Neubauer, B.; Smith, R. A.; Smol, T.; Striano, P.; Stroud, B.; Vaccarezza, M.; Kluger, G.; Lerche, H.; Fazeli, W. (2019)
    Background: Pathogenic variants in SCN2A are associated with various neurological disorders including epilepsy, autism spectrum disorder and intellectual disability. Few reports have recently described SCN2A-associated episodic ataxia (EA). Our study identifies its broader clinical and genetic spectrum, and describes pharmacological approaches. Results: We report 21 patients with SCN2A-associated EA, of which 9 are unpublished cases. The large majority of patients present with epileptic seizures (18/21, 86%), often starting within the first three months of life (12/18, 67%). In contrast, onset of episodic ataxia ranged from 10 months to 14 years of age. The frequency of EA episodes ranged from brief, daily events up to 1-2 episodes per year each lasting several weeks. Potential triggers include minor head traumas and sleep deprivation. Cognitive outcome is favorable in most patients with normal or mildly impaired cognitive development in 17/21 patients (81%). No clear genotype-phenotype correlations were identified in this cohort. However, two mutational hotspots were identified, i.e. 7/21 patients (33%) harbor the identical pathogenic variant p.A263V, whereas 5/21 (24%) carry pathogenic variants that affect the S4 segment and its cytoplasmic loop within the domain IV. In addition, we identified six novel pathogenic variants in SCN2A. While acetazolamide was previously reported as beneficial in SCN2A-associated EA in one case, our data show a conflicting response in 8 additional patients treated with acetazolamide: three of them profited from acetazolamide treatment, while 5/8 did not. Conclusions: Our study describes the heterogeneous clinical spectrum of SCN2A-associated EA, identifies two mutational hotspots and shows positive effects of acetazolamide in about 50%. (C) 2019 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
  • 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.
  • Tsuiko, O.; Noukas, M.; Zilina, O.; Hensen, K.; Tapanainen, J. S.; Magi, R.; Kals, M.; Kivistik, P. A.; Haller-Kikkatalo, K.; Salumets, A.; Kurg, A. (2016)
    Can spontaneous premature ovarian failure (POF) patients derived from population-based biobanks reveal the association between copy number variations (CNVs) and POF? CNVs can hamper the functional capacity of ovaries by disrupting key genes and pathways essential for proper ovarian function. POF is defined as the cessation of ovarian function before the age of 40 years. POF is a major reason for female infertility, although its cause remains largely unknown. The current retrospective CNV study included 301 spontaneous POF patients and 3188 control individuals registered between 2003 and 2014 at Estonian Genome Center at the University of Tartu (EGCUT) biobank. DNA samples from 301 spontaneous POF patients were genotyped by Illumina HumanCoreExome (258 samples) and HumanOmniExpress (43 samples) BeadChip arrays. Genotype and phenotype information was drawn from the EGCUT for the 3188 control population samples, previously genotyped with HumanCNV370 and HumanOmniExpress BeadChip arrays. All identified CNVs were subjected to functional enrichment studies for highlighting the POF pathogenesis. Real-time quantitative PCR was used to validate a subset of CNVs. Whole-exome sequencing was performed on six patients carrying hemizygous deletions that encompass genes essential for meiosis or folliculogenesis. Eleven novel microdeletions and microduplications that encompass genes relevant to POF were identified. For example, FMN2 (1q43) and SGOL2 (2q33.1) are essential for meiotic progression, while TBP (6q27), SCARB1 (12q24.31), BNC1 (15q25) and ARFGAP3 (22q13.2) are involved in follicular growth and oocyte maturation. The importance of recently discovered hemizygous microdeletions of meiotic genes SYCE1 (10q26.3) and CPEB1 (15q25.2) in POF patients was also corroborated. This is a descriptive analysis and no functional studies were performed. Anamnestic data obtained from population-based biobank lacked clinical, biological (hormone levels) or ultrasonographical data, and spontaneous POF was predicted retrospectively by excluding known extraovarian causes for premature menopause. The present study, with high number of spontaneous POF cases, provides novel data on associations between the genomic aberrations and premature menopause of ovarian cause and demonstrates that population-based biobanks are powerful source of biological samples and clinical data to reveal novel genetic lesions associated with human reproductive health and disease, including POF. This study was supported by the Estonian Ministry of Education and Research (IUT20-43, IUT20-60, IUT34-16, SF0180027s10 and 9205), Enterprise Estonia (EU30020 and EU48695), Eureka's EUROSTARS programme (NOTED, EU41564), grants from European Union's FP7 Marie Curie Industry-Academia Partnerships and Pathways (IAPP, SARM, |EU324509) and Horizon 2020 innovation programme (WIDENLIFE, 692065), Academy of Finland and the Sigrid Juselius Foundation.
  • Trotta, Luca; Norberg, Anna; Taskinen, Mervi; Beziat, Vivien; Degerman, Sofie; Wartiovaara-Kautto, Ulla; Välimaa, Hannamari; Jahnukainen, Kirsi; Casanova, Jean-Laurent; Seppänen, Mikko; Saarela, Janna; Koskenvuo, Minna; Martelius, Timi (2018)
    Background: The telomere biology disorders (TBDs) include a range of multisystem diseases characterized by mucocutaneous symptoms and bone marrow failure. In dyskeratosis congenita (DKQ, the clinical features of TBDs stem from the depletion of crucial stem cell populations in highly proliferative tissues, resulting from abnormal telomerase function. Due to the wide spectrum of clinical presentations and lack of a conclusive laboratory test it may be challenging to reach a clinical diagnosis, especially if patients lack the pathognomonic clinical features of TBDs. Methods: Clinical sequencing was performed on a cohort of patients presenting with variable immune phenotypes lacking molecular diagnoses. Hypothesis-free whole-exome sequencing (WES) was selected in the absence of compelling diagnostic hints in patients with variable immunological and haematological conditions. Results: In four patients belonging to three families, we have detected five novel variants in known TBD-causing genes (DKC1, TERT and RTEL1). In addition to the molecular findings, they all presented shortened blood cell telomeres. These findings are consistent with the displayed TBD phenotypes, addressing towards the molecular diagnosis and subsequent clinical follow-up of the patients. Conclusions: Our results strongly support the utility of WES-based approaches for routine genetic diagnostics of TBD patients with heterogeneous or atypical clinical presentation who otherwise might remain undiagnosed.
  • Yang, Kun; Wen, Xiaopeng; Mudunuri, Suresh; Varma, G. P. Saradhi; Sablok, Gaurav (2019)
    Plants have an amazing ability to cope with wide variety of stresses by regulating the expression of genes and thus by altering the physiological status. In the past few years, canonical microRNA variants (isomiRs) have been shown to play pivotal roles by acting as regulators of the transcriptional machinery. In the present research, we present Diff isomiRs, a web-based exploratory repository of differential isomiRs across 16 sequenced plant species representing a total of 433 datasets across 21 different stresses and 158 experimental states. Diff isomiRs provides the high-throughput detection of differential isomiRs using mapping-based and model-based differential analysis revealing a total of 16,157 and 2,028 differential isomiRs, respectively. Easy-to-use and web-based exploration of differential isomiRs provides several features such as browsing of the differential isomiRs according to stress or species, as well as association of the differential isomiRs to targets and plant endogenous target mimics (PeTMs). Diff isomiRs also provides the relationship between the canonical miRNAs, isomiRs and the miRNA-target interactions. This is the first web-based large-scale repository for browsing differential isomiRs and will facilitate better understanding of the regulatory role of the isomiRs with respect to the canonical microRNAs. Diff isomiRs can be accessed at: www.mcr.org.in/diffisomirs.
  • Viinikainen, Jutta; Bryson, Alex; Böckerman, Petri; Elovainio, Marko; Hutri-Kahonen, Nina; Juonala, Markus; Lehtimaki, Terho; Pahkala, Katja; Rovio, Suvi; Pulkki-Råback, Laura; Raitakari, Olli; Pehkonen, Jaakko (2020)
    A burgeoning body of literature suggests that poor childhood health leads to adverse health outcomes. lower educational attainment and weaker labour market outcomes in adulthood. We focus on an important but under-researched topic, which is the role played by infection-related hospitalization (IRH) in childhood and its links to labour market outcomes later in life. The participants aged 24-30 years in 2001 N =1706 were drawn from the Young Finns Study, which includes comprehensive registry data on IRHs in childhood at ages 0-18 years. These data are linked to longitudinal registry information on labour market outcomes (2001-2012) and parental background (1980). The estimations were performed using ordinary least squares (OLS). The results showed that having an additional IRH is associated with lower log earnings (b = 95% confidence interval (CI): -0.193; -0.026). fewer years of being employed (b = -0.018. 95% CI: -0.031; -0.005). a higher probability of receiving any social income transfers (b = 0.012, 95 % CI: -0.002; 0.026) and larger social income transfers, conditional on receiving any (b = 0.085,95 % CI: 0.025; 0.145). IRHs are negatively linked to human capital accumulation. which explains a considerable part of the observed associations between IRHs and labour market outcomes. We did not find support for the hypothesis that adult health mediates the link. (C) 2020 The Authors. Published by Elsevier B.V.
  • Viinikainen, Jutta; Bryson, Alex; Böckerman, Petri; Elovainio, Marko; Pitkänen, Niina; Pulkki-Råback, Laura; Lehtimäki, Terho; Raitakari, Olli; Pehkonen, Jaakko (2018)
    Using participants (N=1733) drawn from the nationally representative longitudinal Young Finns Study (YFS) we estimate the effect of education on depressive symptoms. In 2007, when the participants were between 30 and 45 years old, they reported their depressive symptoms using a revised version of Beck's Depression Inventory. Education was measured using register information on the highest completed level of education in 2007, which was converted to years of education. To identify a causal relationship between education and depressive symptoms we use an instrumental variables approach (Mendelian randomization, MR) with a genetic risk score as an instrument for years of education. The genetic risk score was based on 74 genetic variants, which were associated with years of education in a genome-wide association study (GWAS). Because the genetic variants are randomly assigned at conception, they induce exogenous variation in years of education and thus identify a causal effect if the assumptions of the MR approach are met. In Ordinary Least Squares (OLS) estimation years of education in 2007 were negatively associated with depressive symptoms in 2007 (b=-0.027, 95% Confidence Interval (CI)=-0.040, -0.015). However, the results based on Mendelian randomization suggested that the effect is not causal (b=0.017; 95% CI=-0.144, 0.178). This indicates that omitted variables correlated with education and depression may bias the linear regression coefficients and exogenous variation in education caused by differences in genetic make-up does not seem to protect against depressive symptoms.
  • Peyrard-Janvid, Myriam; Leslie, Elizabeth J.; Kousa, Youssef A.; Smith, Tiffany L.; Dunnwald, Martine; Magnusson, Mans; Lentz, Brian A.; Unneberg, Per; Fransson, Ingegerd; Koillinen, Hannele K.; Rautio, Jorma; Pegelow, Marie; Karsten, Agneta; Basel-Vanagaite, Lina; Gordon, William; Andersen, Bogi; Svensson, Thomas; Murray, Jeffrey C.; Cornell, Robert A.; Kere, Juha; Schutte, Brian C. (2014)
  • Perez-Palma, Eduardo; Saarentaus, Elmo; Ravoet, Marie; De Ferrari, Giancarlo V.; Nuernberg, Peter; Isidor, Bertrand; Neubauer, Bernd A.; Lal, Dennis (2018)
    Objective After the recent publication of the first patients with disease-associated missense variants in the GRIN2D gene, we evaluate the effect of copy number variants (CNVs) overlapping this gene toward the presentation of neurodevelopmental disorders (NDDs). Methods We exploredClinVar (number ofCNVs = 50,794) andDECIPHER (number ofCNVs = 28,085) clinical databases of genomic variations for patients with copy number changes overlapping the GRIN2D gene at the 19q13.33 locus and evaluated their respective phenotype alongside their frequency, gene content, and expression, with publicly available reference databases. Results We identified 11 patients with microduplications at the 19q13.33 locus. The majority of CNVs arose de novo, and comparable CNVs are not present in control databases. All patients were reported to have NDDs and dysmorphic features as the most common clinical phenotype (N = 8/11), followed by seizures (N = 6/11) and intellectual disability (N = 5/11). All duplications shared a consensus region of 405 kb overlapping 13 genes. After screening for duplication tolerance in control populations, positive gene brain expression, and gene dosage sensitivity analysis, we highlight 4 genes for future evaluation: CARD8, C19orf68, KDELR1, and GRIN2D, which are promising candidates for disease causality. Furthermore, investigation of the literature especially supports GRIN2D as the best candidate gene. Conclusions Our study presents dup19q13.33 as a novel duplication syndrome locus associated with NDDs. CARD8, C19orf68, KDELR1, and GRIN2D are promising candidates for functional follow-up.
  • European Soc Human Genetics; European Council Legal Med; European Soc Cardiology Working; European Reference Network Rare; Assoc European Cardiovasc; Fellmann, Florence; van El, Carla G.; Sajantila, Antti (2019)
    Sudden cardiac death (SCD) accounts for 10-20% of total mortality, i.e., one in five individuals will eventually die suddenly. Given the substantial genetic component of SCD in younger cases, postmortem genetic testing may be particularly useful in elucidating etiological factors in the cause of death in this subset. The identification of genes responsible for inherited cardiac diseases have led to the organization of cardiogenetic consultations in many countries worldwide. Expert recommendations are available, emphasizing the importance of genetic testing and appropriate information provision of affected individuals, as well as their relatives. However, the context of postmortem genetic testing raises some particular ethical, legal, and practical (including economic or financial) challenges. The Public and Professional Policy Committee of the European Society of Human Genetics (ESHG), together with international experts, developed recommendations on management of SCD after a workshop sponsored by the Brocher Foundation and ESHG in November 2016. These recommendations have been endorsed by the ESHG Board, the European Council of Legal Medicine, the European Society of Cardiology working group on myocardial and pericardial diseases, the ERN GUARD-HEART, and the Association for European Cardiovascular Pathology. They emphasize the importance of increasing the proportion of both medical and medicolegal autopsies and educating the professionals. Multidisciplinary collaboration is of utmost importance. Public funding should be allocated to reach these goals and allow public health evaluation.