Browsing by Subject "SEQUENCE VARIANTS"

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  • Lek, Monkol; Karczewski, Konrad J.; Minikel, Eric V.; Samocha, Kaitlin E.; Banks, Eric; Fennell, Timothy; O'Donnell-Luria, Anne H.; Ware, James S.; Hill, Andrew J.; Cummings, Beryl B.; Tukiainen, Taru; Birnbaum, Daniel P.; Kosmicki, Jack A.; Duncan, Laramie E.; Estrada, Karol; Zhao, Fengmei; Zou, James; Pierce-Hollman, Emma; Berghout, Joanne; Cooper, David N.; Deflaux, Nicole; DePristo, Mark; Do, Ron; Flannick, Jason; Fromer, Menachem; Gauthier, Laura; Goldstein, Jackie; Gupta, Namrata; Howrigan, Daniel; Kiezun, Adam; Kurki, Mitja I.; Moonshine, Ami Levy; Natarajan, Pradeep; Orozeo, Lorena; Peloso, Gina M.; Poplin, Ryan; Rivas, Manuel A.; Ruano-Rubio, Valentin; Rose, Samuel A.; Ruderfer, Douglas M.; Shakir, Khalid; Stenson, Peter D.; Stevens, Christine; Thomas, Brett P.; Tiao, Grace; Tusie-Luna, Maria T.; Weisburd, Ben; Palotie, Aarno; Tuomilehto, Jaakko; Daly, Mark J.; Exome Aggregation Consortium (2016)
    Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. Here we describe the aggregation and analysis of high-quality exome (protein-coding region) DNA sequence data for 60,706 individuals of diverse ancestries generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We have used this catalogue to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; identifying 3,230 genes with near-complete depletion of predicted protein-truncating variants, with 72% of these genes having no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human 'knockout' variants in protein-coding genes.
  • EuroEPINOMICS-RES Consortium; Heyne, Henrike O.; Linnankivi, Tarja; Palotie, Aarno; Daly, Mark J.; Lehesjoki, Anna-Elina (2018)
    Epilepsy is a frequent feature of neurodevelopmental disorders (NDDs), but little is known about genetic differences between NDDs with and without epilepsy. We analyzed de novo variants (DNVs) in 6,753 parent-offspring trios ascertained to have different NDDs. In the subset of 1,942 individuals with NDDs with epilepsy, we identified 33 genes with a significant excess of DNVs, of which SNAP25 and GABRB2 had previously only limited evidence of disease association. Joint analysis of all individuals with NDDs also implicated CACNA1E as a novel disease-associated gene. Comparing NDDs with and without epilepsy, we found missense DNVs, DNVs in specific genes, age of recruitment, and severity of intellectual disability to be associated with epilepsy. We further demonstrate the extent to which our results affect current genetic testing as well as treatment, emphasizing the benefit of accurate genetic diagnosis in NDDs with epilepsy.
  • CHD Exome Consortium; Consortium Genetics Smoking; EPIC-CVD Consortium; Understanding Soc Sci Grp; Brazel, David M.; Jiang, Yu; Hughey, Jordan M.; Loukola, Anu; Qaiser, Beenish; Kaprio, Jaakko; Kontto, Jukka; Perola, Markus; Dunning, Alison M. (2019)
    BACKGROUND: Smoking and alcohol use have been associated with common genetic variants in multiple loci. Rare variants within these loci hold promise in the identification of biological mechanisms in substance use. Exome arrays and genotype imputation can now efficiently genotype rare nonsynonymous and loss of function variants. Such variants are expected to have deleterious functional consequences and to contribute to disease risk. METHODS: We analyzed similar to 250,000 rare variants from 16 independent studies genotyped with exome arrays and augmented this dataset with imputed data from the UK Biobank. Associations were tested for five phenotypes: cigarettes per day, pack-years, smoking initiation, age of smoking initiation, and alcoholic drinks per week. We conducted stratified heritability analyses, single-variant tests, and gene-based burden tests of nonsynonymous/loss-of-function coding variants. We performed a novel fine-mapping analysis to winnow the number of putative causal variants within associated loci. RESULTS: Meta-analytic sample sizes ranged from 152,348 to 433,216, depending on the phenotype. Rare coding variation explained 1.1% to 2.2% of phenotypic variance, reflecting 11% to 18% of the total single nucleotide polymorphism heritability of these phenotypes. We identified 171 genome-wide associated loci across all phenotypes. Fine mapping identified putative causal variants with double base-pair resolution at 24 of these loci, and between three and 10 variants for 65 loci. Twenty loci contained rare coding variants in the 95% credible intervals. CONCLUSIONS: Rare coding variation significantly contributes to the heritability of smoking and alcohol use. Fine-mapping genome-wide association study loci identifies specific variants contributing to the biological etiology of substance use behavior.
  • Petersen, Jessica L.; Mickelson, James R.; Rendahl, Aaron K.; Valberg, Stephanie J.; Andersson, Lisa S.; Axelsson, Jeanette; Bailey, Ernie; Bannasch, Danika; Binns, Matthew M.; Borges, Alexandre S.; Brama, Pieter; Machado, Artur da Camara; Capomaccio, Stefano; Cappelli, Katia; Cothran, E. Gus; Distl, Ottmar; Fox-Clipsham, Laura; Graves, Kathryn T.; Guerin, Gerard; Haase, Bianca; Hasegawa, Telhisa; Hemmann, Karin; Hill, Emmeline W.; Leeb, Tosso; Lindgren, Gabriella; Lohi, Hannes; Lopes, Maria Susana; McGivney, Beatrice A.; Mikko, Sofia; Orr, Nicholas; Penedo, M. Cecilia T.; Piercy, Richard J.; Raekallio, Marja; Rieder, Stefan; Røed, Knut H.; Swinburne, June; Tozaki, Teruaki; Vaudin, Mark; Wade, Claire M.; McCue, Molly E. (2013)
  • Hancock, D. B.; Guo, Y.; Reginsson, G. W.; Gaddis, N. C.; Lutz, S. M.; Sherva, R.; Loukola, A.; Minica, C. C.; Markunas, C. A.; Han, Y.; Young, K. A.; Gudbjartsson, D. F.; Gu, F.; McNeil, D. W.; Qaiser, B.; Glasheen, C.; Olson, S.; Landi, M. T.; Madden, P. A. F.; Farrer, L. A.; Vink, J.; Saccone, N. L.; Neale, M. C.; Kranzler, H. R.; McKay, J.; Hung, R. J.; Amos, C. I.; Marazita, M. L.; Boomsma, D. I.; Baker, T. B.; Gelernter, J.; Kaprio, J.; Caporaso, N. E.; Thorgeirsson, T. E.; Hokanson, J. E.; Bierut, L. J.; Stefansson, K.; Johnson, E. O. (2018)
    Cigarette smoking is a leading cause of preventable mortality worldwide. Nicotine dependence, which reduces the likelihood of quitting smoking, is a heritable trait with firmly established associations with sequence variants in nicotine acetylcholine receptor genes and at other loci. To search for additional loci, we conducted a genome-wide association study (GWAS) meta-analysis of nicotine dependence, totaling 38,602 smokers (28,677 Europeans/European Americans and 9925 African Americans) across 15 studies. In this largest-ever GWAS meta-analysis for nicotine dependence and the largest-ever cross-ancestry GWAS meta-analysis for any smoking phenotype, we reconfirmed the well-known CHRNA5-CHRNA3-CHRNB4 genes and further yielded a novel association in the DNA methyltransferase gene DNMT3B. The intronic DNMT3B rs910083-C allele (frequency = 44-77%) was associated with increased risk of nicotine dependence at P = 3.7 x 10(-8) (odds ratio (OR) = 1.06 and 95% confidence interval (CI) = 1.04-1.07 for severe vs mild dependence). The association was independently confirmed in the UK Biobank (N = 48,931) using heavy vs never smoking as a proxy phenotype (P = 3.6 x 10(-4), OR = 1.05, and 95% CI = 1.02-1.08). Rs910083-C is also associated with increased risk of squamous cell lung carcinoma in the International Lung Cancer Consortium (N = 60,586, meta-analysis P = 0.0095, OR = 1.05, and 95% CI = 1.01-1.09). Moreover, rs910083-C was implicated as a cis-methylation quantitative trait locus (QTL) variant associated with higher DNMT3B methylation in fetal brain (N = 166, P = 2.3 x 10(-26)) and a cis-expression QTL variant associated with higher DNMT3B expression in adult cerebellum from the Genotype-Tissue Expression project (N = 103, P = 3.0 x 10(-6)) and the independent Brain eQTL Almanac (N = 134, P = 0.028). This novel DNMT3B cis-acting QTL variant highlights the importance of genetically influenced regulation in brain on the risks of nicotine dependence, heavy smoking and consequent lung cancer.
  • He, Liang; Pitkäniemi, Janne; Heikkila, Kauko; Chou, Yi-Ling; Madden, Pamela A. F.; Korhonen, Tellervo; Sarin, Antti-Pekka; Ripatti, Samuli; Kaprio, Jaakko; Loukola, Anu (2016)
    Background: Various pivotal stages in smoking behavior can be identified, including initiation, conversion from experimenting to established use, development of tolerance, and cessation. Previous studies have shown high heritability for age of smoking initiation and cessation; however, time-to-event genome-wide association studies aiming to identify underpinning genes that accelerate or delay these transitions are missing to date. Methods: We investigated which single nucleotide polymorphisms (SNPs) across the whole genome contribute to the hazard ratio of transition between different stages of smoking behavior by performing time-to-event analyses within a large Finnish twin family cohort (N = 1962), and further conducted mediation analyses of plausible intermediate traits for significant SNPs. Results: Genome-wide significant signals were detected for three of the four transitions: (1) for smoking cessation on 10p14 (P = 4.47e-08 for rs72779075 flanked by RP11-575N15 and GATA3), (2) for tolerance on 11p13 (P = 1.29e-08 for rs11031684 in RP1-65P5.1), mediated by smoking quantity, and on 9q34.12 (P = 3.81e-08 for rs2304808 in FUBP3), independent of smoking quantity, and (3) for smoking initiation on 19q13.33 (P = 3.37e-08 for rs73050610 flanked by TRPM4 and SLC6A16) in analysis adjusted for first time sensations. Although our top SNPs did not replicate, another SNP in the TRPM4-SLC6A16 gene region showed statistically significant association after region-based multiple testing correction in an independent Australian twin family sample. Conclusion: Our results suggest that the functional effect of the TRPM4-SLC6A16 gene region deserves further investigation, and that complex neurotransmitter networks including dopamine and glutamate may play a critical role in smoking initiation. Moreover, comparison of these results implies that genetic contributions to the complex smoking behavioral phenotypes vary among the transitions.
  • Patel, Kashyap A.; Kettunen, Jarno; Laakso, Markku; Stancakova, Alena; Laver, Thomas W.; Colclough, Kevin; Johnson, Matthew B.; Abramowicz, Marc; Groop, Leif; Miettinen, Paivi J.; Shepherd, Maggie H.; Flanagan, Sarah E.; Ellard, Sian; Inagaki, Nobuya; Hattersley, Andrew T.; Tuomi, Tiinamaija; Cnop, Miriam; Weedon, Michael N. (2017)
    Finding new causes of monogenic diabetes helps understand glycaemic regulation in humans. To find novel genetic causes of maturity-onset diabetes of the young (MODY), we sequenced MODY cases with unknown aetiology and compared variant frequencies to large public databases. From 36 European patients, we identify two probands with novel RFX6 heterozygous nonsense variants. RFX6 protein truncating variants are enriched in the MODY discovery cohort compared to the European control population within ExAC (odds ratio = 131, P = 1 x 10(-4)). We find similar results in non-Finnish European (n = 348, odds ratio = 43, P = 5 x 10(-5)) and Finnish (n = 80, odds ratio = 22, P = 1 x 10(-6)) replication cohorts. RFX6 heterozygotes have reduced penetrance of diabetes compared to common HNF1A and HNF4A-MODY mutations (27, 70 and 55% at 25 years of age, respectively). The hyperglycaemia results from beta-cell dysfunction and is associated with lower fasting and stimulated gastric inhibitory polypeptide (GIP) levels. Our study demonstrates that heterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance.
  • Perez-Palma, Eduardo; May, Patrick; Iqbal, Sumaiya; Niestroj, Lisa-Marie; Du, Juanjiangmeng; Heyne, Henrike O.; Castrillon, Jessica A.; O'Donnell-Luria, Anne; Nuernberg, Peter; Palotie, Aarno; Daly, Mark; Lal, Dennis (2020)
    Missense variant interpretation is challenging. Essential regions for protein function are conserved among gene-family members, and genetic variants within these regions are potentially more likely to confer risk to disease. Here, we generated 2871 gene-family protein sequence alignments involving 9990 genes and performed missense variant burden analyses to identify novel essential protein regions. We mapped 2,219,811 variants from the general population into these alignments and compared their distribution with 76,153 missense variants from patients. With this gene-family approach, we identified 465 regions enriched for patient variants spanning 41,463 amino acids in 1252 genes. As a comparison, by testing the same genes individually, we identified fewer patient variant enriched regions, involving only 2639 amino acids and 215 genes. Next, we selected de novo variants from 6753 patients with neurodevelopmental disorders and 1911 unaffected siblings and observed an 8.33-fold enrichment of patient variants in our identified regions (95% C.I. = 3.90-Inf, P-value= 2.72 x 10(-11)). By using the complete ClinVar variant set, we found that missense variants inside the identified regions are 106-fold more likely to be classified as pathogenic in comparison to benign classification (OR = 106.15, 95% C.I = 70.66-Inf, P-value <2.2x10(-16)). All pathogenic variant enriched regions (PERs) identified are available online through "PER viewer," a user-friendly online platform for interactive data mining, visualization, and download. In summary, our gene-family burden analysis approach identified novel PERs in protein sequences. This annotation can empower variant interpretation.
  • Hemminki, Kari; Srivastava, Aayushi; Rachakonda, Sivaramakrishna; Bandapalli, Obul; Nagore, Eduardo; Hemminki, Akseli; Kumar, Rajiv (2020)
    Background When germline mutations are suspected as causal in cancer, patient DNA may be sequenced to detect variants in relevant genes. If a particular mutation has not been reported in reliable family studies, genetic counselors are facing a dilemma of appropriately informing patients. Many sequencing facilities provide an interpretation of the findings based on the available sequence databases or on prediction tools that are curated from bioinformatics and mechanistic datasets. The counseling dilemma is exacerbated if the pedigree data are not informative but the in silico predictions suggest pathogenicity. Methods We present here a real world example of the c.256G > ACDKN2Avariant, which was detected in one melanoma patient where two siblings were diagnosed with melanoma in situ. We investigated a detailed family history of the affected siblings in order to survey probability of the cancer risks within the context to this mutation. Results This c.256G > ACDKN2Avariant was detected in one of the brothers and in the melanoma-free mother while the other brother in the family tested negative. The variant had been previously described in one patient from a melanoma family. In the family under investigation, the mother's 16 first-and second-degree relatives had survived past the median onset age for melanoma and none presented melanoma. We tested the variant using multiple bioinformatic tools that all predicted deleteriousness of the variant. The genetic counseling report to the melanoma patient stated that theCDKN2Avariant was 'likely pathogenic' and the disease was defined as 'likely hereditary melanoma'. Conclusions The pedigree data showed at the most a low penetrance variant, which, if taken into consideration, might have altered the provided diagnosis. When dealing with 'practically' unknown variants the counselors would be advised to incorporate a detailed family history rather than basing predictions on functionality provided by sequencing facilities.
  • Parsons, Michael T.; Tudini, Emma; Li, Hongyan; Hahnen, Eric; Wappenschmidt, Barbara; Feliubadaló, Lidia; Aalfs, Cora M.; Agata, Simona; Aittomäki, Kristiina; Alducci, Elisa; Alonso-Cerezo, María Concepción; Arnold, Norbert; Auber, Bernd; Austin, Rachel; Azzollini, Jacopo; Balmaña, Judith; Barbieri, Elena; Bartram, Claus R.; Blanco, Ana; Blümcke, Britta; Bonache, Sandra; Bonanni, Bernardo; Borg, Åke; Bortesi, Beatrice; Brunet, Joan; Bruzzone, Carla; Bucksch, Karolin; Cagnoli, Giulia; Caldés, Trinidad; Caliebe, Almuth; Caligo, Maria A.; Calvello, Mariarosaria; Capone, Gabriele L.; Caputo, Sandrine M.; Carnevali, Ileana; Carrasco, Estela; Caux-Moncoutier, Virginie; Cavalli, Pietro; Cini, Giulia; Clarke, Edward M.; Concolino, Paola; Cops, Elisa J.; Cortesi, Laura; Couch, Fergus J.; Darder, Esther; de la Hoya, Miguel; Dean, Michael; Debatin, Irmgard; del Valle, Jesús; Delnatte, Capucine; Derive, Nicolas; Diez, Orland; Ditsch, Nina; Domchek, Susan M.; Dutrannoy, Véronique; Eccles, Diana M.; Ehrencrona, Hans; Enders, Ute; Evans, D. Gareth; Faust, Ulrike; Felbor, Ute; Feroce, Irene; Fine, Miriam; Galvao, Henrique C.R.; Gambino, Gaetana; Gehrig, Andrea; Gensini, Francesca; Gerdes, Anne-Marie; Germani, Aldo; Giesecke, Jutta; Gismondi, Viviana; Gómez, Carolina; Gómez Garcia, Encarna B.; González, Sara; Grau, Elia; Grill, Sabine; Gross, Eva; Guerrieri-Gonzaga, Aliana; Guillaud-Bataille, Marine; Gutiérrez-Enríquez, Sara; Haaf, Thomas; Hackmann, Karl; Hansen, Thomas V.O.; Harris, Marion; Hauke, Jan; Heinrich, Tilman; Hellebrand, Heide; Herold, Karen N.; Honisch, Ellen; Horvath, Judit; Houdayer, Claude; Hübbel, Verena; Iglesias, Silvia; Izquierdo, Angel; James, Paul A.; Janssen, Linda A.M.; Jeschke, Udo; Kaulfuß, Silke; Keupp, Katharina; Kiechle, Marion; Kölbl, Alexandra; Krieger, Sophie; Kruse, Torben A.; Kvist, Anders; Lalloo, Fiona; Larsen, Mirjam; Lattimore, Vanessa L.; Lautrup, Charlotte; Ledig, Susanne; Leinert, Elena; Lewis, Alexandra L.; Lim, Joanna; Loeffler, Markus; López-Fernández, Adrià; Lucci-Cordisco, Emanuela; Maass, Nicolai; Manoukian, Siranoush; Marabelli, Monica; Matricardi, Laura; Meindl, Alfons; Michelli, Rodrigo D.; Moghadasi, Setareh; Moles-Fernández, Alejandro; Montagna, Marco; Montalban, Gemma; Monteiro, Alvaro N.; Montes, Eva; Mori, Luigi; Moserle, Lidia; Müller, Clemens R.; Mundhenke, Christoph; Naldi, Nadia; Nathanson, Katherine L.; Navarro, Matilde; Nevanlinna, Heli; Nichols, Cassandra B.; Niederacher, Dieter; Nielsen, Henriette R.; Ong, Kai-ren; Pachter, Nicholas; Palmero, Edenir I.; Papi, Laura; Pedersen, Inge Sokilde; Peissel, Bernard; Pérez-Segura, Pedro; Pfeifer, Katharina; Pineda, Marta; Pohl-Rescigno, Esther; Poplawski, Nicola K.; Porfirio, Berardino; Quante, Anne S.; Ramser, Juliane; Reis, Rui M.; Revillion, Françoise; Rhiem, Kerstin; Riboli, Barbara; Ritter, Julia; Rivera, Daniela; Rofes, Paula; Rump, Andreas; Salinas, Monica; Sánchez de Abajo, Ana María; Schmidt, Gunnar; Schoenwiese, Ulrike; Seggewiß, Jochen; Solanes, Ares; Steinemann, Doris; Stiller, Mathias; Stoppa-Lyonnet, Dominique; Sullivan, Kelly J.; Susman, Rachel; Sutter, Christian; Tavtigian, Sean V.; Teo, Soo H.; Teulé, Alex; Thomassen, Mads; Tibiletti, Maria Grazia; Tognazzo, Silvia; Toland, Amanda E.; Tornero, Eva; Törngren, Therese; Torres-Esquius, Sara; Toss, Angela; Trainer, Alison H.; van Asperen, Christi J.; van Mackelenbergh, Marion T.; Varesco, Liliana; Vargas-Parra, Gardenia; Varon, Raymonda; Vega, Ana; Velasco, Ángela; Vesper, Anne-Sophie; Viel, Alessandra; Vreeswijk, Maaike P.G.; Wagner, Sebastian A.; Waha, Anke; Walker, Logan C.; Walters, Rhiannon J.; Wang-Gohrke, Shan; Weber, Bernhard H.F.; Weichert, Wilko; Wieland, Kerstin; Wiesmüller, Lisa; Witzel, Isabell; Wöckel, Achim; Woodward, Emma R.; Zachariae, Silke; Zampiga, Valentina; Zeder-Göß, Christine; Investigators, KConFab; Lázaro, Conxi; De Nicolo, Arcangela; Radice, Paolo; Engel, Christoph; Schmutzler, Rita K.; Goldgar, David E.; Spurdle, Amanda B. (2019)
    Abstract The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared to information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known non-pathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification. This article is protected by copyright. All rights reserved.
  • Saccone, Nancy L.; Culverhouse, Robert C.; Schwantes-An, Tae-Hwi; Cannon, Dale S.; Chen, Xiangning; Cichon, Sven; Giegling, Ina; Han, Shizhong; Han, Younghun; Keskitalo-Vuokko, Kaisu; Kong, Xiangyang; Landi, Maria Teresa; Ma, Jennie Z.; Short, Susan E.; Stephens, Sarah H.; Stevens, Victoria L.; Sun, Lingwei; Wang, Yufei; Wenzlaff, Angela S.; Aggen, Steven H.; Breslau, Naomi; Broderick, Peter; Chatterjee, Nilanjan; Chen, Jingchun; Heath, Andrew C.; Heliovaara, Markku; Hoft, Nicole R.; Hunter, David J.; Jensen, Majken K.; Martin, Nicholas G.; Montgomery, Grant W.; Niu, Tianhua; Payne, Thomas J.; Palotie, Leena; Pergadia, Michele L.; Rice, John P.; Sherva, Richard; Spitz, Margaret R.; Sun, Juzhong; Wang, Jen C.; Weiss, Robert B.; Wheeler, William; Witt, Stephanie H.; Yang, Bao-Zhu; Caporaso, Neil E.; Ehringer, Marissa A.; Eisen, Tim; Gapstur, Susan M.; Gelernter, Joel; Houlston, Richard; Kaprio, Jaakko; Kendler, Kenneth S.; Kraft, Peter; Leppert, Mark F.; Li, Ming D.; Madden, Pamela A. F.; Noethen, Markus M.; Pillai, Sreekumar; Rietschel, Marcella; Rujescu, Dan; Schwartz, Ann; Amos, Christopher I.; Bierut, Laura J. (2010)
  • Costantini, Alice; Skarp, Sini; Kampe, Anders; Mäkitie, Riikka E.; Pettersson, Maria; Männikkö, Minna; Jiao, Hong; Taylan, Fulya; Lindstrand, Anna; Mäkitie, Outi (2018)
    Early-onset osteoporosis is characterized by low bone mineral density (BMD) and fractures since childhood or young adulthood. Several monogenic forms have been identified but the contributing genes remain inadequately characterized. In search for novel variants and novel candidate loci, we screened a cohort of 70 young subjects with mild to severe skeletal fragility for rare copy-number variants (CNVs). Our study cohort included 15 subjects with primary osteoporosis before age 30 years and 55 subjects with a pathological fracture history and low or normal BMD before age 16 years. A custom-made high-resolution comparative genomic hybridization array with enriched probe density in >1,150 genes important for bone metabolism and ciliary function was used to search for CNVs. We identified altogether 14 rare CNVs. Seven intronic aberrations were classified as likely benign. Five CNVs of unknown clinical significance affected coding regions of genes not previously associated with skeletal fragility (ETV1-DGKB, AGBL2, ATM, RPS6KL1-PGF, and SCN4A). Finally, two CNVs were pathogenic and likely pathogenic, respectively: a 4 kb deletion involving exons 1-4 of COL1A2 (NM_000089.3) and a 12.5 kb duplication of exon 3 in PLS3 (NM_005032.6). Although both genes have been linked to monogenic forms of osteoporosis, COL1A2 deletions are rare and PLS3 duplications have not been described previously. Both CNVs were identified in subjects with significant osteoporosis and segregated with osteoporosis within the families. Our study expands the number of pathogenic CNVs in monogenic skeletal fragility and shows the validity of targeted CNV screening to potentially pinpoint novel candidate loci in early-onset osteoporosis.
  • Artigas, Maria Soler; Wain, Louise V.; Miller, Suzanne; Kheirallah, Abdul Kader; Huffman, Jennifer E.; Ntalla, Ioanna; Shrine, Nick; Obeidat, Ma'en; Trochet, Holly; McArdle, Wendy L.; Alves, Alexessander Couto; Hui, Jennie; Zhao, Jing Hua; Joshi, Peter K.; Teumer, Alexander; Albrecht, Eva; Imboden, Medea; Rawal, Rajesh; Lopez, Lorna M.; Marten, Jonathan; Enroth, Stefan; Surakka, Ida; Polasek, Ozren; Lyytikainen, Leo-Pekka; Granell, Raquel; Hysi, Pirro G.; Flexeder, Claudia; Mahajan, Anubha; Beilby, John; Bosse, Yohan; Brandsma, Corry-Anke; Campbell, Harry; Gieger, Christian; Glaeser, Sven; Gonzalez, Juan R.; Grallert, Harald; Hammond, Chris J.; Harris, Sarah E.; Hartikainen, Anna-Liisa; Heliovaara, Markku; Henderson, John; Hocking, Lynne; Horikoshi, Momoko; Hutri-Kahonen, Nina; Ingelsson, Erik; Johansson, Asa; Kemp, John P.; Kolcic, Ivana; Kumar, Ashish; Ripatti, Samuli; UK BiLEVE (2015)
    Lung function measures are used in the diagnosis of chronic obstructive pulmonary disease. In 38,199 European ancestry individuals, we studied genome-wide association of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC with 1000 Genomes Project (phase 1)-imputed genotypes and followed up top associations in 54,550 Europeans. We identify 14 novel loci (P <5 x 10(-8)) in or near ENSA, RNU5F-1, KCNS3, AK097794, ASTN2, LHX3, CCDC91, TBX3, TRIP11, RIN3, TEKT5, LTBP4, MN1 and AP1S2, and two novel signals at known loci NPNT and GPR126, providing a basis for new understanding of the genetic determinants of these traits and pulmonary diseases in which they are altered.
  • Leinonen, Jaakko T.; Crotti, Lia; Djupsjobacka, Aurora; Castelletti, Silvia; Junna, Nella; Ghidoni, Alice; Tuiskula, Annukka M.; Spazzolini, Carla; Dagradi, Federica; Viitasalo, Matti; Kontula, Kimmo; Kotta, Maria-Christina; Widen, Elisabeth; Swan, Heikki; Schwartz, Peter J. (2018)
    Background: Ventricular fibrillation (VF) is a major cause of sudden cardiac death. In some cases clinical investigations fail to identify the underlying cause and the event is classified as idiopathic (IVF). Since mutations in arrhythmia-associated genes frequently determine arrhythmia susceptibility, screening for disease-predisposing variants could improve IVF diagnostics. Methods and results: The study included 76 Finnish and Italian patients with a mean age of 31.2 years at the time of the VF event, collected between the years 1996-2016 and diagnosed with idiopathic, out-of-hospital VF. Using whole-exome sequencing (WES) and next-generation sequencing (NGS) approaches, we aimed to identify genetic variants potentially contributing to the life-threatening arrhythmias of these patients. Combining the results from the two study populations, we identified pathogenic or likely pathogenic variants residing in the RYR2, CACNA1C and DSP genes in 7 patients (9%). Most of them(5, 71%) were found in the RYR2 gene, associated with catecholaminergic polymorphic ventricular tachycardia (CPVT). These genetic findings prompted clinical investigations leading to disease reclassification. Additionally, in 9 patients (11.8%) we detected 10 novel or extremely rare (MAF <0.005%) variants that were classified as of unknown significance (VUS). Conclusion: The results of our study suggest that a subset of patients originally diagnosed with IVF may carry clinically-relevant variants in genes associated with cardiac channelopathies and cardiomyopathies. Although misclassification of other cardiac channelopathies as IVF appears rare, our findings indicate that the possibility of CPVT as the underlying disease entity should be carefully evaluated in IVF patients. (C) 2017 Elsevier B.V. All rights reserved.