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3. Runs of Homozygosity Implicate Autozygosity as a Schizophrenia Risk Factor.

Author

Keller, Matthew C., Simonson, Matthew A., Ripke, Stephan, Neale, Ben M., Gejman, Pablo V., Howrigan, Daniel P., Sang Hong Lee, Lencz, Todd, Levinson, Douglas F., and Sullivan, Patrick F.

Subjects
CHROMOSOMES, POPULATION genetics, SCHIZOPHRENIA, ETIOLOGY of diseases, GENETIC disorders
Abstract

Autozygosity occurs when two chromosomal segments that are identical from a common ancestor are inherited from each parent. This occurs at high rates in the offspring of mates who are closely related (inbreeding), but also occurs at lower levels among the offspring of distantly related mates. Here, we use runs of homozygosity in genome-wide SNP data to estimate the proportion of the autosome that exists in autozygous tracts in 9,388 cases with schizophrenia and 12,456 controls. We estimate that the odds of schizophrenia increase by ~7% for every 1% increase in genome-wide autozygosity. This association is not due to one or a few regions, but results from many autozygous segments spread throughout the genome, and is consistent with a role for multiple recessive or partially recessive alleles in the etiology of schizophrenia. Such a bias towards recessivity suggests that alleles that increase the risk of schizophrenia have been selected against over evolutionary time. [ABSTRACT FROM AUTHOR]

Published
2012
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4. Large-scale genomic analyses link reproductive ageing to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair

Author

Day, Felix R., Ruth, Katherine S., Thompson, Deborah J., Lunetta, Kathryn L., Pervjakova, Natalia, Chasman, Daniel I., Stolk, Lisette, Finucane, Hilary K., Sulem, Patrick, Bulik-Sullivan, Brendan, Esko, Tõnu, Johnson, Andrew D., Elks, Cathy E., Franceschini, Nora, He, Chunyan, Altmaier, Elisabeth, Brody, Jennifer A., Franke, Lude L., Huffman, Jennifer E., Keller, Margaux F., McArdle, Patrick F., Nutile, Teresa, Porcu, Eleonora, Robino, Antonietta, Rose, Lynda M., Schick, Ursula M., Smith, Jennifer A., Teumer, Alexander, Traglia, Michela, Vuckovic, Dragana, Yao, Jie, Zhao, Wei, Albrecht, Eva, Amin, Najaf, Corre, Tanguy, Hottenga, Jouke-Jan, Mangino, Massimo, Smith, Albert V., Tanaka, Toshiko, Abecasis, Goncalo, Andrulis, Irene L., Anton-Culver, Hoda, Antoniou, Antonis C., Arndt, Volker, Arnold, Alice M., Barbieri, Caterina, Beckmann, Matthias W., Beeghly-Fadiel, Alicia, Benitez, Javier, Bernstein, Leslie, Bielinski, Suzette J., Blomqvist, Carl, Boerwinkle, Eric, Bogdanova, Natalia V., Bojesen, Stig E., Bolla, Manjeet K., Borresen-Dale, Anne-Lise, Boutin, Thibaud S, Brauch, Hiltrud, Brenner, Hermann, Brüning, Thomas, Burwinkel, Barbara, Campbell, Archie, Campbell, Harry, Chanock, Stephen J., Chapman, J. Ross, Chen, Yii-Der Ida, Chenevix-Trench, Georgia, Couch, Fergus J., Coviello, Andrea D., Cox, Angela, Czene, Kamila, Darabi, Hatef, De Vivo, Immaculata, Demerath, Ellen W., Dennis, Joe, Devilee, Peter, Dörk, Thilo, dos-Santos-Silva, Isabel, Dunning, Alison M., Eicher, John D., Fasching, Peter A., Faul, Jessica D., Figueroa, Jonine, Flesch-Janys, Dieter, Gandin, Ilaria, Garcia, Melissa E., García-Closas, Montserrat, Giles, Graham G., Girotto, Giorgia G., Goldberg, Mark S., González-Neira, Anna, Goodarzi, Mark O., Grove, Megan L., Gudbjartsson, Daniel F., Guénel, Pascal, Guo, Xiuqing, Haiman, Christopher A., Hall, Per, Hamann, Ute, Henderson, Brian E., Hocking, Lynne J., Hofman, Albert, Homuth, Georg, Hooning, Maartje J., Hopper, John L., Hu, Frank B., Huang, Jinyan, Humphreys, Keith, Hunter, David J., Jakubowska, Anna, Jones, Samuel E., Kabisch, Maria, Karasik, David, Knight, Julia A., Kolcic, Ivana, Kooperberg, Charles, Kosma, Veli-Matti, Kriebel, Jennifer, Kristensen, Vessela, Lambrechts, Diether, Langenberg, Claudia, Li, Jingmei, Li, Xin, Lindström, Sara, Liu, Yongmei, Luan, Jian’an, Lubinski, Jan, Mägi, Reedik, Mannermaa, Arto, Manz, Judith, Margolin, Sara, Marten, Jonathan, Martin, Nicholas G., Masciullo, Corrado, Meindl, Alfons, Michailidou, Kyriaki, Mihailov, Evelin, Milani, Lili, Milne, Roger L., Müller-Nurasyid, Martina, Nalls, Michael, Neale, Ben M., Nevanlinna, Heli, Neven, Patrick, Newman, Anne B., Nordestgaard, Børge G., Olson, Janet E., Padmanabhan, Sandosh, Peterlongo, Paolo, Peters, Ulrike, Petersmann, Astrid, Peto, Julian, Pharoah, Paul D.P., Pirastu, Nicola N., Pirie, Ailith, Pistis, Giorgio, Polasek, Ozren, Porteous, David, Psaty, Bruce M., Pylkäs, Katri, Radice, Paolo, Raffel, Leslie J., Rivadeneira, Fernando, Rudan, Igor, Rudolph, Anja, Ruggiero, Daniela, Sala, Cinzia F., Sanna, Serena, Sawyer, Elinor J., Schlessinger, David, Schmidt, Marjanka K., Schmidt, Frank, Schmutzler, Rita K., Schoemaker, Minouk J., Scott, Robert A., Seynaeve, Caroline M., Simard, Jacques, Sorice, Rossella, Southey, Melissa C., Stöckl, Doris, Strauch, Konstantin, Swerdlow, Anthony, Taylor, Kent D., Thorsteinsdottir, Unnur, Toland, Amanda E., Tomlinson, Ian, Truong, Thérèse, Tryggvadottir, Laufey, Turner, Stephen T., Vozzi, Diego, Wang, Qin, Wellons, Melissa, Willemsen, Gonneke, Wilson, James F., Winqvist, Robert, Wolffenbuttel, Bruce B.H.R., Wright, Alan F., Yannoukakos, Drakoulis, Zemunik, Tatijana, Zheng, Wei, Zygmunt, Marek, Bergmann, Sven, Boomsma, Dorret I., Buring, Julie E., Ferrucci, Luigi, Montgomery, Grant W., Gudnason, Vilmundur, Spector, Tim D., van Duijn, Cornelia M, Alizadeh, Behrooz Z., Ciullo, Marina, Crisponi, Laura, Easton, Douglas F., Gasparini, Paolo P., Gieger, Christian, Harris, Tamara B., Hayward, Caroline, Kardia, Sharon L.R., Kraft, Peter, McKnight, Barbara, Metspalu, Andres, Morrison, Alanna C., Reiner, Alex P., Ridker, Paul M., Rotter, Jerome I., Toniolo, Daniela, Uitterlinden, André G., Ulivi, Sheila, Völzke, Henry, Wareham, Nicholas J., Weir, David R., Yerges-Armstrong, Laura M., Price, Alkes L., Stefansson, Kari, Visser, Jenny A., Ong, Ken K., Chang-Claude, Jenny, Murabito, Joanne M., Perry, John R.B., and Murray, Anna

Abstract

Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in ~70,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two harbouring additional rare missense alleles of large effect. We found enrichment of signals in/near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses revealed a major association with DNA damage-response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomisation analyses supported a causal effect of later ANM on breast cancer risk (~6% risk increase per-year, P=3×10−14), likely mediated by prolonged sex hormone exposure, rather than DDR mechanisms.

Published
2015
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5. Runs of Homozygosity Implicate Autozygosity as a Schizophrenia Risk Factor

Author

Nancy Buccola, Andrew McQuillin, James Walters, Sven Cichon, Ole A. Andreassen, Markus Nöthen, Hywel Williams, Danielle Posthuma, Inez Myin-Germeys, Draga Toncheva, Anders Rosengren, Paul Lichtenstein, Sang Hong Lee, Johan H Thygesen, Stanley Zammit, Morten Mattingsdal, Ingrid Agartz, Robert Freedman, Donald Black, Pierandrea Muglia, Richard Bruggeman, MATTHEW KELLER, Manuel Mattheisen, Nicholas James Bass, Sarah Bergen, Andrew McIntosh, Bryan Mowry, Srdjan Djurovic, Stephan Ripke, Todd Lencz, Adult Psychiatry, ANS - Amsterdam Neuroscience, Psychiatrie & Neuropsychologie, RS: MHeNs School for Mental Health and Neuroscience, Keller, Matthew C, Simonson, Matthew A, Ripke, Stephan, Neale, Ben M, Gejman, Pablo V, Howrigan, Daniel P, Lee, Sang Hong, Lencz, Todd, Levinson, Douglas F, Sullivan, Patrick F, Schizophrenia Psychiatric Genome-Wide Association Study Consortium, Germeys, Inez, Functional Genomics, and Neuroscience Campus Amsterdam - integrative Analysis & Modeling

Subjects
Evolutionary Genetics, Male, Cancer Research, Population genetics, Genome-wide association study, heritability, Runs of Homozygosity, polymorphism, 0302 clinical medicine, Risk Factors, GWAS, recessivity, Genetics (clinical), Genetics & Heredity, Genetics, Psychiatry, 0303 health sciences, Homozygote, recessive alleles, autozygosity, Mental Health, disease genetics, Medicine, Female, Inbreeding, Research Article, lcsh:QH426-470, Offspring, European Continental Ancestry Group, inbreeding, SNP, Genes, Recessive, Biology, Polymorphism, Single Nucleotide, White People, 03 medical and health sciences, ddc:570, Genome-Wide Association Studies, Humans, Genetic Predisposition to Disease, Allele, QH426, Molecular Biology, Ecology, Evolution, Behavior and Systematics, Alleles, 030304 developmental biology, Evolutionary Biology, Autosome, Genome, Human, Haplotype, Psychoses, Human Genetics, R1, schizophrenia, lcsh:Genetics, Haplotypes, genome-wide association studies, RC0321, Schizophrenia, 030217 neurology & neurosurgery, Population Genetics
Abstract

Autozygosity occurs when two chromosomal segments that are identical from a common ancestor are inherited from each parent. This occurs at high rates in the offspring of mates who are closely related (inbreeding), but also occurs at lower levels among the offspring of distantly related mates. Here, we use runs of homozygosity in genome-wide SNP data to estimate the proportion of the autosome that exists in autozygous tracts in 9,388 cases with schizophrenia and 12,456 controls. We estimate that the odds of schizophrenia increase by ∼17% for every 1% increase in genome-wide autozygosity. This association is not due to one or a few regions, but results from many autozygous segments spread throughout the genome, and is consistent with a role for multiple recessive or partially recessive alleles in the etiology of schizophrenia. Such a bias towards recessivity suggests that alleles that increase the risk of schizophrenia have been selected against over evolutionary time., Author Summary Inbreeding occurs when genetic relatives have offspring. Because all humans are related to one another, even if very distantly, all people are inbred to various degrees. From a genetic standpoint, it is well known that inbreeding increases the risk that a child will have a rare recessive genetic disease, but there is also increasing interest in understanding whether inbreeding is a risk factor for more common, complex disorders such as schizophrenia. In this investigation, we used single-nucleotide polymorphism data to quantify the degree to which 9,388 schizophrenia cases and 12,456 controls were inbred, and we tested the hypothesis that people whose genome shows higher evidence of being inbred are at higher risk of having schizophrenia. We estimate that the odds of schizophrenia increase by ∼17% for every 1% increase in inbreeding. This finding is consistent with a role for multiple recessive or partially recessive alleles in the etiology of schizophrenia, and it suggests that genetic variants that increase the risk of schizophrenia have been selected against over evolutionary time.

Published
2012

6. SynGO: An Evidence-Based, Expert-Curated Knowledge Base for the Synapse.

Author

Koopmans F, van Nierop P, Andres-Alonso M, Byrnes A, Cijsouw T, Coba MP, Cornelisse LN, Farrell RJ, Goldschmidt HL, Howrigan DP, Hussain NK, Imig C, de Jong APH, Jung H, Kohansalnodehi M, Kramarz B, Lipstein N, Lovering RC, MacGillavry H, Mariano V, Mi H, Ninov M, Osumi-Sutherland D, Pielot R, Smalla KH, Tang H, Tashman K, Toonen RFG, Verpelli C, Reig-Viader R, Watanabe K, van Weering J, Achsel T, Ashrafi G, Asi N, Brown TC, De Camilli P, Feuermann M, Foulger RE, Gaudet P, Joglekar A, Kanellopoulos A, Malenka R, Nicoll RA, Pulido C, de Juan-Sanz J, Sheng M, Südhof TC, Tilgner HU, Bagni C, Bayés À, Biederer T, Brose N, Chua JJE, Dieterich DC, Gundelfinger ED, Hoogenraad C, Huganir RL, Jahn R, Kaeser PS, Kim E, Kreutz MR, McPherson PS, Neale BM, O'Connor V, Posthuma D, Ryan TA, Sala C, Feng G, Hyman SE, Thomas PD, Smit AB, and Verhage M

Subjects
Animals, Brain physiology, Databases, Genetic, Humans, Knowledge Bases, Synaptic Potentials physiology, Synaptosomes, Brain cytology, Gene Ontology, Proteomics, Software, Synapses physiology
Abstract

Synapses are fundamental information-processing units of the brain, and synaptic dysregulation is central to many brain disorders ("synaptopathies"). However, systematic annotation of synaptic genes and ontology of synaptic processes are currently lacking. We established SynGO, an interactive knowledge base that accumulates available research about synapse biology using Gene Ontology (GO) annotations to novel ontology terms: 87 synaptic locations and 179 synaptic processes. SynGO annotations are exclusively based on published, expert-curated evidence. Using 2,922 annotations for 1,112 genes, we show that synaptic genes are exceptionally well conserved and less tolerant to mutations than other genes. Many SynGO terms are significantly overrepresented among gene variations associated with intelligence, educational attainment, ADHD, autism, and bipolar disorder and among de novo variants associated with neurodevelopmental disorders, including schizophrenia. SynGO is a public, universal reference for synapse research and an online analysis platform for interpretation of large-scale -omics data (https://syngoportal.org and http://geneontology.org)., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Published
2019
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