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Exome Sequencing to Detect Rare Variants Associated With General Cognitive Ability: A Pilot Study
- Michelle Luciano, Victoria Svinti, Archie Campbell, Riccardo E. Marioni, Caroline Hayward, Alan F. Wright, Martin S. Taylor, David J. Porteous, Pippa Thomson, James G.D. Prendergast, Nicholas D. Hastie, Susan M. Farrington, Generation Scotland, Malcolm G. Dunlop, Ian J. Deary
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- Journal:
- Twin Research and Human Genetics / Volume 18 / Issue 2 / April 2015
- Published online by Cambridge University Press:
- 06 March 2015, pp. 117-125
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- Article
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Variation in human cognitive ability is of consequence to a large number of health and social outcomes and is substantially heritable. Genetic linkage, genome-wide association, and copy number variant studies have investigated the contribution of genetic variation to individual differences in normal cognitive ability, but little research has considered the role of rare genetic variants. Exome sequencing studies have already met with success in discovering novel trait-gene associations for other complex traits. Here, we use exome sequencing to investigate the effects of rare variants on general cognitive ability. Unrelated Scottish individuals were selected for high scores on a general component of intelligence (g). The frequency of rare genetic variants (in n = 146) was compared with those from Scottish controls (total n = 486) who scored in the lower to middle range of the g distribution or on a proxy measure of g. Biological pathway analysis highlighted enrichment of the mitochondrial inner membrane component and apical part of cell gene ontology terms. Global burden analysis showed a greater total number of rare variants carried by high g cases versus controls, which is inconsistent with a mutation load hypothesis whereby mutations negatively affect g. The general finding of greater non-synonymous (vs. synonymous) variant effects is in line with evolutionary hypotheses for g. Given that this first sequencing study of high g was small, promising results were found, suggesting that the study of rare variants in larger samples would be worthwhile.
Contributors
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- By Joanne R. Adler, David A. Alexander, Laurence Alison, Catherine C. Ayoub, Peter Banister, Anthony R. Beech, Amanda Biggs, Julian Boon, Adrian Bowers, Neil Brewer, Eric Broekaert, Paula Brough, Jennifer M. Brown, Kevin Browne, Elizabeth A. Campbell, David Canter, Michael Carlin, Shihning Chou, Martin A. Conway, Claire Cooke, David Cooke, Ilse Derluyn, Robert J. Edelmann, Vincent Egan, Tom Ellis, Marie Eyre, David P. Farrington, Seena Fazel, Daniel B. Fishman, Victoria Follette, Katarina Fritzon, Elizabeth Gilchrist, Nathan D. Gillard, Renée Gobeil, Agnieszka Golec de Zavala, Jane Goodman-Delahunty, Lynsey Gozna, Don Grubin, Gisli H. Gudjonsson, Helinä Häkkänen-Nyholm, Guy Hall, Nathan Hall, Roisin Hall, Sean Hammond, Leigh Harkins, Grant T. Harris, Camilla Herbert, Robert D. Hoge, Todd E. Hogue, Clive R. Hollin, Lorraine Hope, Miranda A. H. Horvath, Kevin Howells, Carol A. Ireland, Jane L. Ireland, Mark Kebbell, Michael King, Bruce D. Kirkcaldy, Heidi La Bash, Cara Laney, William R. Lindsay, Elizabeth F. Loftus, L. E. Marshall, W. L. Marshall, James McGuire, Neil McKeganey, T. M. McMillan, Mary McMurran, Joav Merrick, Becky Milne, Joanne M. Nadkarni, Claire Nee, M. D. O’Brien, William O’Donohue, Darragh O’Neill, Jane Palmer, Adria Pearson, Derek Perkins, Devon L. L. Polaschek, Louise E. Porter, Charlotte C. Powell, Graham E. Powell, Martine Powell, Christine Puckering, Ethel Quayle, Vernon L. Quinsey, Marnie E. Rice, Randall Richardson-Vejlgaard, Richard Rogers, Louis B Schlesinger, Carolyn Semmler, G. A. Serran, Ralph C. Serin, John L. Taylor, Max Taylor, Brian Thomas-Peter, Paul A. Tiffin, Graham Towl, Rosie Travers, Arlene Vetere, Graham Wagstaff, Helen Wakeling, Fiona Warren, Brandon C. Welsh, David Wexler, Margaret Wilson, Dan Yarmey, Susan Young
- Edited by Jennifer M. Brown, London School of Economics and Political Science, Elizabeth A. Campbell, University of Glasgow
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- Book:
- The Cambridge Handbook of Forensic Psychology
- Published online:
- 06 July 2010
- Print publication:
- 29 April 2010, pp xix-xxiii
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17 - Genetics of colorectal cancer
- Edited by Alan Wright, MRC Human Genetics Unit, Edinburgh, Nicholas Hastie, MRC Human Genetics Unit, Edinburgh
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- Book:
- Genes and Common Diseases
- Published online:
- 17 August 2009
- Print publication:
- 02 August 2007, pp 245-267
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Summary
Introduction
Colorectal cancer is a major public health problem in the developed world and is becoming increasingly prevalent in developing countries. The current annual world incidence is around 950 000 cases (Globocan, 2000). It is the most common cause of early cancer death in the non-smoking population. Recent developments have led to the isolation of a number of moderate- to high-risk cancer susceptibility genes for the disease. Identifying people with high-risk alleles offers real opportunities for application of preventive measures. Intensive surveillance to detect early cancer, or even prevent cancer by polyp removal, can be targeted by genotype information. Surgical intervention and chemoprevention guided by genetic information are also likely to be part of future armaments used to combat the disease. The last ten years has seen a number of exciting developments in understanding key molecular events involved in colorectal cancer susceptibility, which are beginning to provide new insight into the fundamental basis of the disease. In this chapter we will describe the major advances and how they are impacting diagnosis and clinical management of colorectal cancer.
Colorectal cancer epidemiology
The multifactorial etiology of colorectal cancer involves environmental factors as well as genetic susceptibility (see Chapter 14). There are large differences in global prevalence of the disease, which is generally four times higher in developed countries than in developing countries (IARC, WHO, 1997). Incidence rates also vary according to ethnicity (American Cancer Society, 2002), however the observed variation between countries is primarily due to the role of environmental factors.