Exome Sequencing to Detect Rare Variants Associated With General Cognitive Ability: A Pilot Study
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...
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Veröffentlicht in: | Twin research and human genetics 2015-04, Vol.18 (2), p.117-125 |
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creator | Luciano, Michelle Svinti, Victoria Campbell, Archie Marioni, Riccardo E. Hayward, Caroline Wright, Alan F. Taylor, Martin S. Porteous, David J. Thomson, Pippa Prendergast, James G.D. Hastie, Nicholas D. Farrington, Susan M. Scotland, Generation Dunlop, Malcolm G. Deary, Ian J. |
description | 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. |
doi_str_mv | 10.1017/thg.2015.10 |
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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.</description><identifier>ISSN: 1832-4274</identifier><identifier>EISSN: 1839-2628</identifier><identifier>DOI: 10.1017/thg.2015.10</identifier><identifier>PMID: 25744449</identifier><language>eng</language><publisher>Cambridge, UK: Cambridge University Press</publisher><subject>Adult ; Age ; Aged ; Cognition ; Cognitive ability ; Copy number ; Exome ; Families & family life ; Female ; Genes ; Genetic diversity ; Genomes ; High-Throughput Nucleotide Sequencing ; Humans ; Intelligence ; Intelligence - genetics ; Male ; Medical research ; Mental health ; Middle Aged ; Mitochondria ; Mutation ; Pilot Projects ; Quantitative Trait Loci ; Research ethics ; Scotland ; Standard deviation</subject><ispartof>Twin research and human genetics, 2015-04, Vol.18 (2), p.117-125</ispartof><rights>Copyright © The Author(s) 2015</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c392t-ea72916899ce49b1e9cd551b05cab542bbf71d7eb2d4cf50254cd700a3a499cb3</citedby><cites>FETCH-LOGICAL-c392t-ea72916899ce49b1e9cd551b05cab542bbf71d7eb2d4cf50254cd700a3a499cb3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.cambridge.org/core/product/identifier/S1832427415000109/type/journal_article$$EHTML$$P50$$Gcambridge$$H</linktohtml><link.rule.ids>164,314,778,782,27907,27908,55611</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25744449$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Luciano, Michelle</creatorcontrib><creatorcontrib>Svinti, Victoria</creatorcontrib><creatorcontrib>Campbell, Archie</creatorcontrib><creatorcontrib>Marioni, Riccardo E.</creatorcontrib><creatorcontrib>Hayward, Caroline</creatorcontrib><creatorcontrib>Wright, Alan F.</creatorcontrib><creatorcontrib>Taylor, Martin S.</creatorcontrib><creatorcontrib>Porteous, David J.</creatorcontrib><creatorcontrib>Thomson, Pippa</creatorcontrib><creatorcontrib>Prendergast, James G.D.</creatorcontrib><creatorcontrib>Hastie, Nicholas D.</creatorcontrib><creatorcontrib>Farrington, Susan M.</creatorcontrib><creatorcontrib>Scotland, Generation</creatorcontrib><creatorcontrib>Dunlop, Malcolm G.</creatorcontrib><creatorcontrib>Deary, Ian J.</creatorcontrib><title>Exome Sequencing to Detect Rare Variants Associated With General Cognitive Ability: A Pilot Study</title><title>Twin research and human genetics</title><addtitle>Twin Res Hum Genet</addtitle><description>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.</description><subject>Adult</subject><subject>Age</subject><subject>Aged</subject><subject>Cognition</subject><subject>Cognitive ability</subject><subject>Copy number</subject><subject>Exome</subject><subject>Families & family life</subject><subject>Female</subject><subject>Genes</subject><subject>Genetic diversity</subject><subject>Genomes</subject><subject>High-Throughput Nucleotide Sequencing</subject><subject>Humans</subject><subject>Intelligence</subject><subject>Intelligence - genetics</subject><subject>Male</subject><subject>Medical research</subject><subject>Mental health</subject><subject>Middle Aged</subject><subject>Mitochondria</subject><subject>Mutation</subject><subject>Pilot Projects</subject><subject>Quantitative Trait Loci</subject><subject>Research ethics</subject><subject>Scotland</subject><subject>Standard deviation</subject><issn>1832-4274</issn><issn>1839-2628</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNptkE1LJDEQhoO4-DF68i4BL4K0JumkM_E2jKO7ICi6ux6bJF0zRro7mqTF-ffGdVZBrEtVwVNvVb0I7VFyTAmVJ-l-ccwIFblbQ1t0XKqCVWy8_q9mBWeSb6LtGB8IKSVVZANtMiF5DrWF9OzFd4Bv4WmA3rp-gZPHZ5DAJnyjA-C_Ojjdp4gnMXrrdIIG37l0jy-gh6BbPPWL3iX3DHhiXOvS8hRP8LVrfcK3aWiWO-jHXLcRdld5hP6cz35PfxaXVxe_ppPLwpaKpQK0ZIpWY6UscGUoKNsIQQ0RVhvBmTFzSRsJhjXczgVhgttGEqJLzfOMKUfo8F33Mfj8TEx156KFttU9-CHWtJKcEVEqmdGDL-iDH0Kfr6uZHKuqUvmWTB29Uzb4GAPM68fgOh2WNSX1m_N1dr5-cz53md5faQ6mg-aD_W91BoqVnO5McM0CPrd-J_gKau2M3g</recordid><startdate>20150401</startdate><enddate>20150401</enddate><creator>Luciano, Michelle</creator><creator>Svinti, Victoria</creator><creator>Campbell, Archie</creator><creator>Marioni, Riccardo E.</creator><creator>Hayward, Caroline</creator><creator>Wright, Alan F.</creator><creator>Taylor, Martin S.</creator><creator>Porteous, David J.</creator><creator>Thomson, Pippa</creator><creator>Prendergast, James G.D.</creator><creator>Hastie, Nicholas D.</creator><creator>Farrington, Susan M.</creator><creator>Scotland, Generation</creator><creator>Dunlop, Malcolm G.</creator><creator>Deary, Ian J.</creator><general>Cambridge University Press</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>LK8</scope><scope>M7P</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>20150401</creationdate><title>Exome Sequencing to Detect Rare Variants Associated With General Cognitive Ability: A Pilot Study</title><author>Luciano, Michelle ; 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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.</abstract><cop>Cambridge, UK</cop><pub>Cambridge University Press</pub><pmid>25744449</pmid><doi>10.1017/thg.2015.10</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Adult Age Aged Cognition Cognitive ability Copy number Exome Families & family life Female Genes Genetic diversity Genomes High-Throughput Nucleotide Sequencing Humans Intelligence Intelligence - genetics Male Medical research Mental health Middle Aged Mitochondria Mutation Pilot Projects Quantitative Trait Loci Research ethics Scotland Standard deviation |
title | Exome Sequencing to Detect Rare Variants Associated With General Cognitive Ability: A Pilot Study |
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