Large-scale genomics unveil polygenic architecture of human cortical surface area

Chi Hua Chen; Qian Peng; Andrew J. Schork; Min Tzu Lo; Chun Chieh Fan; Yunpeng Wang; Rahul S. Desikan; Francesco Bettella; Donald J. Hagler; Lars T. Westlye; William S. Kremen; Terry L. Jernigan; Stephanie Le Hellard; Vidar M. Steen; Thomas Espeseth; Matt Huentelman; Asta K. Håberg; Ingrid Agartz; Srdjan Djurovic; Ole A. Andreassen; Nicholas Schork; Anders M. Dale; Connor McCabe; Linda Chang; Natacha Akshoomoff; Erik Newman; Thomas Ernst; Peter Van Zijl; Joshua Kuperman; Sarah Murray; Cinnamon Bloss; Mark Appelbaum; Anthony Gamst; Wesley Thompson; Hauke Bartsch; Michael Weiner; Paul Aisen; Ronald Petersen; Clifford R. Jack; William Jagust; John Q. Trojanowki; Arthur W. Toga; Laurel Beckett; Robert C. Green; Andrew J. Saykin; John Morris; Leslie M. Shaw; Zaven Khachaturian; Greg Sorensen; Maria Carrillo; Lew Kuller; Marc Raichle; Steven Paul; Peter Davies; Howard Fillit; Franz Hefti; Davie Holtzman; M. Marcel Mesulman; William Potter; Peter J. Snyder; Adam Schwartz; Tom Montine; Ronald G. Thomas; Michael Donohue; Sarah Walter; Devon Gessert; Tamie Sather; Gus Jiminez; Danielle Harvey; Matthew Bernstein; Nick Fox; Paul Thompson; Norbert Schuff; Charles DeCarli; Bret Borowski; Jeff Gunter; Matt Senjem; Prashanthi Vemuri; David Jones; Kejal Kantarci; Chad Ward; Robert A. Koeppe; Norm Foster; Eric M. Reiman; Kewei Chen; Chet Mathis; Susan Landau; Nigel J. Cairns; Erin Householder; Lisa Taylor-Reinwald; Virginia M.Y. Lee; Magdalena Korecka; Michal Figurski; Karen Crawford; Scott Neu; Tatiana M. Foroud; Steven Potkin; Li Shen; Kelley Faber; Sungeun Kim; Kwangsik Nho; Leon Thal; Richard Frank; Neil Buckholtz; Marilyn Albert; John Hsiao

doi:10.1038/ncomms8549

Large-scale genomics unveil polygenic architecture of human cortical surface area

Chi Hua Chen, Qian Peng, Andrew J. Schork, Min Tzu Lo, Chun Chieh Fan, Yunpeng Wang, Rahul S. Desikan, Francesco Bettella, Donald J. Hagler, Lars T. Westlye, William S. Kremen, Terry L. Jernigan, Stephanie Le Hellard, Vidar M. Steen, Thomas Espeseth, Matt Huentelman, Asta K. Håberg, Ingrid Agartz, Srdjan Djurovic, Ole A. AndreassenNicholas Schork, Anders M. Dale, Connor McCabe, Linda Chang, Natacha Akshoomoff, Erik Newman, Thomas Ernst, Peter Van Zijl, Joshua Kuperman, Sarah Murray, Cinnamon Bloss, Mark Appelbaum, Anthony Gamst, Wesley Thompson, Hauke Bartsch, Michael Weiner, Paul Aisen, Ronald Petersen, Clifford R. Jack, William Jagust, John Q. Trojanowki, Arthur W. Toga, Laurel Beckett, Robert C. Green, Andrew J. Saykin, John Morris, Leslie M. Shaw, Zaven Khachaturian, Greg Sorensen, Maria Carrillo, Lew Kuller, Marc Raichle, Steven Paul, Peter Davies, Howard Fillit, Franz Hefti, Davie Holtzman, M. Marcel Mesulman, William Potter, Peter J. Snyder, Adam Schwartz, Tom Montine, Ronald G. Thomas, Michael Donohue, Sarah Walter, Devon Gessert, Tamie Sather, Gus Jiminez, Danielle Harvey, Matthew Bernstein, Nick Fox, Paul Thompson, Norbert Schuff, Charles DeCarli, Bret Borowski, Jeff Gunter, Matt Senjem, Prashanthi Vemuri, David Jones, Kejal Kantarci, Chad Ward, Robert A. Koeppe, Norm Foster, Eric M. Reiman, Kewei Chen, Chet Mathis, Susan Landau, Nigel J. Cairns, Erin Householder, Lisa Taylor-Reinwald, Virginia M.Y. Lee, Magdalena Korecka, Michal Figurski, Karen Crawford, Scott Neu, Tatiana M. Foroud, Steven Potkin, Li Shen, Kelley Faber, Sungeun Kim, Kwangsik Nho, Leon Thal, Richard Frank, Neil Buckholtz, Marilyn Albert, John Hsiao

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Abstract

Little is known about how genetic variation contributes to neuroanatomical variability, and whether particular genomic regions comprising genes or evolutionarily conserved elements are enriched for effects that influence brain morphology. Here, we examine brain imaging and single-nucleotide polymorphisms (SNPs) data from ∼ 2,700 individuals. We show that a substantial proportion of variation in cortical surface area is explained by additive effects of SNPs dispersed throughout the genome, with a larger heritable effect for visual and auditory sensory and insular cortices (h² ∼ 0.45). Genome-wide SNPs collectively account for, on average, about half of twin heritability across cortical regions (N = 466 twins). We find enriched genetic effects in or near genes. We also observe that SNPs in evolutionarily more conserved regions contributed significantly to the heritability of cortical surface area, particularly, for medial and temporal cortical regions. SNPs in less conserved regions contributed more to occipital and dorsolateral prefrontal cortices.

Original language	English
Article number	7549
Journal	Nature communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms8549
State	Published - Jul 20 2015

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Chen, C. H., Peng, Q., Schork, A. J., Lo, M. T., Fan, C. C., Wang, Y., Desikan, R. S., Bettella, F., Hagler, D. J., Westlye, L. T., Kremen, W. S., Jernigan, T. L., Le Hellard, S., Steen, V. M., Espeseth, T., Huentelman, M., Håberg, A. K., Agartz, I., Djurovic, S., ... Hsiao, J. (2015). Large-scale genomics unveil polygenic architecture of human cortical surface area. Nature communications, 6, Article 7549. https://doi.org/10.1038/ncomms8549

@article{fe882122df7543129078cd10a5121e07,

title = "Large-scale genomics unveil polygenic architecture of human cortical surface area",

abstract = "Little is known about how genetic variation contributes to neuroanatomical variability, and whether particular genomic regions comprising genes or evolutionarily conserved elements are enriched for effects that influence brain morphology. Here, we examine brain imaging and single-nucleotide polymorphisms (SNPs) data from ∼ 2,700 individuals. We show that a substantial proportion of variation in cortical surface area is explained by additive effects of SNPs dispersed throughout the genome, with a larger heritable effect for visual and auditory sensory and insular cortices (h2 ∼ 0.45). Genome-wide SNPs collectively account for, on average, about half of twin heritability across cortical regions (N = 466 twins). We find enriched genetic effects in or near genes. We also observe that SNPs in evolutionarily more conserved regions contributed significantly to the heritability of cortical surface area, particularly, for medial and temporal cortical regions. SNPs in less conserved regions contributed more to occipital and dorsolateral prefrontal cortices.",

author = "Chen, {Chi Hua} and Qian Peng and Schork, {Andrew J.} and Lo, {Min Tzu} and Fan, {Chun Chieh} and Yunpeng Wang and Desikan, {Rahul S.} and Francesco Bettella and Hagler, {Donald J.} and Westlye, {Lars T.} and Kremen, {William S.} and Jernigan, {Terry L.} and {Le Hellard}, Stephanie and Steen, {Vidar M.} and Thomas Espeseth and Matt Huentelman and H{\aa}berg, {Asta K.} and Ingrid Agartz and Srdjan Djurovic and Andreassen, {Ole A.} and Nicholas Schork and Dale, {Anders M.} and Connor McCabe and Linda Chang and Natacha Akshoomoff and Erik Newman and Thomas Ernst and {Van Zijl}, Peter and Joshua Kuperman and Sarah Murray and Cinnamon Bloss and Mark Appelbaum and Anthony Gamst and Wesley Thompson and Hauke Bartsch and Michael Weiner and Paul Aisen and Ronald Petersen and Jack, {Clifford R.} and William Jagust and Trojanowki, {John Q.} and Toga, {Arthur W.} and Laurel Beckett and Green, {Robert C.} and Saykin, {Andrew J.} and John Morris and Shaw, {Leslie M.} and Zaven Khachaturian and Greg Sorensen and Maria Carrillo and Lew Kuller and Marc Raichle and Steven Paul and Peter Davies and Howard Fillit and Franz Hefti and Davie Holtzman and Mesulman, {M. Marcel} and William Potter and Snyder, {Peter J.} and Adam Schwartz and Tom Montine and Thomas, {Ronald G.} and Michael Donohue and Sarah Walter and Devon Gessert and Tamie Sather and Gus Jiminez and Danielle Harvey and Matthew Bernstein and Nick Fox and Paul Thompson and Norbert Schuff and Charles DeCarli and Bret Borowski and Jeff Gunter and Matt Senjem and Prashanthi Vemuri and David Jones and Kejal Kantarci and Chad Ward and Koeppe, {Robert A.} and Norm Foster and Reiman, {Eric M.} and Kewei Chen and Chet Mathis and Susan Landau and Cairns, {Nigel J.} and Erin Householder and Lisa Taylor-Reinwald and Lee, {Virginia M.Y.} and Magdalena Korecka and Michal Figurski and Karen Crawford and Scott Neu and Foroud, {Tatiana M.} and Steven Potkin and Li Shen and Kelley Faber and Sungeun Kim and Kwangsik Nho and Leon Thal and Richard Frank and Neil Buckholtz and Marilyn Albert and John Hsiao",

note = "Funding Information: Funded by the National Institute of Mental Health R01MH100351; National Institute on Aging R01AG22381, AG18386 and AG18384; NARSAD Young Investigator award (C.-H.C). Liaison Committee between the Central Norway Regional Health Authority and the Norwegian University of Science and Technology, HUNT administration grants, and National Norwegian Advisory Unit, for functional MRI methods. South East Norway Health Authority (#2013-123), Research Council of Norway (#229129, #213837 and #223273), EU (#602450) and KG Jebsen Foundation. Part of data collection and sharing for this project was funded by the Pediatric Imaging, Neurocognition and Genetics Study (PING), National Institutes of Health Grant RC2DA029475. PING is funded by the National Institute on Drug Abuse and the Eunice Kennedy Shriver National Institute of Child Health & Human Development. PING data are disseminated by the PING Coordinating Center at the Center for Human Development, University of California, San Diego. Part of data collection and sharing for this project was funded by the Alzheimer{\textquoteright}s Disease Neuroimaging initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering and through generous contributions from the following: Alzheimer{\textquoteright}s Association; Alzheimer{\textquoteright}s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd; Janssen Alzheimer Immunotherapy Research & Development, LLC; Johnson & Johnson Pharmaceutical Research & Development LLC; Medpace, Inc.; Merck & Co., Inc.; Meso Scale Diagnostics, LLC; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Synarc Inc.; and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer{\textquoteright}s Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. Publisher Copyright: {\textcopyright} 2015 Macmillan Publishers Limited. All rights reserved.",

year = "2015",

month = jul,

day = "20",

doi = "10.1038/ncomms8549",

language = "English",

volume = "6",

journal = "Nature communications",

issn = "2041-1723",

}

Chen, CH, Peng, Q, Schork, AJ, Lo, MT, Fan, CC, Wang, Y, Desikan, RS, Bettella, F, Hagler, DJ, Westlye, LT, Kremen, WS, Jernigan, TL, Le Hellard, S, Steen, VM, Espeseth, T, Huentelman, M, Håberg, AK, Agartz, I, Djurovic, S, Andreassen, OA, Schork, N, Dale, AM, McCabe, C, Chang, L, Akshoomoff, N, Newman, E, Ernst, T, Van Zijl, P, Kuperman, J, Murray, S, Bloss, C, Appelbaum, M, Gamst, A, Thompson, W, Bartsch, H, Weiner, M, Aisen, P, Petersen, R, Jack, CR, Jagust, W, Trojanowki, JQ, Toga, AW, Beckett, L, Green, RC, Saykin, AJ, Morris, J, Shaw, LM, Khachaturian, Z, Sorensen, G, Carrillo, M, Kuller, L, Raichle, M , Paul, S, Davies, P, Fillit, H, Hefti, F, Holtzman, D, Mesulman, MM, Potter, W, Snyder, PJ, Schwartz, A, Montine, T, Thomas, RG, Donohue, M, Walter, S, Gessert, D, Sather, T, Jiminez, G, Harvey, D, Bernstein, M, Fox, N, Thompson, P, Schuff, N, DeCarli, C, Borowski, B, Gunter, J, Senjem, M, Vemuri, P, Jones, D, Kantarci, K, Ward, C, Koeppe, RA, Foster, N, Reiman, EM, Chen, K, Mathis, C, Landau, S, Cairns, NJ, Householder, E, Taylor-Reinwald, L, Lee, VMY, Korecka, M, Figurski, M, Crawford, K, Neu, S, Foroud, TM, Potkin, S, Shen, L, Faber, K, Kim, S, Nho, K, Thal, L, Frank, R, Buckholtz, N, Albert, M & Hsiao, J 2015, 'Large-scale genomics unveil polygenic architecture of human cortical surface area', Nature communications, vol. 6, 7549. https://doi.org/10.1038/ncomms8549

TY - JOUR

T1 - Large-scale genomics unveil polygenic architecture of human cortical surface area

AU - Chen, Chi Hua

AU - Peng, Qian

AU - Schork, Andrew J.

AU - Lo, Min Tzu

AU - Fan, Chun Chieh

AU - Wang, Yunpeng

AU - Desikan, Rahul S.

AU - Bettella, Francesco

AU - Hagler, Donald J.

AU - Westlye, Lars T.

AU - Kremen, William S.

AU - Jernigan, Terry L.

AU - Le Hellard, Stephanie

AU - Steen, Vidar M.

AU - Espeseth, Thomas

AU - Huentelman, Matt

AU - Håberg, Asta K.

AU - Agartz, Ingrid

AU - Djurovic, Srdjan

AU - Andreassen, Ole A.

AU - Schork, Nicholas

AU - Dale, Anders M.

AU - McCabe, Connor

AU - Chang, Linda

AU - Akshoomoff, Natacha

AU - Newman, Erik

AU - Ernst, Thomas

AU - Van Zijl, Peter

AU - Kuperman, Joshua

AU - Murray, Sarah

AU - Bloss, Cinnamon

AU - Appelbaum, Mark

AU - Gamst, Anthony

AU - Thompson, Wesley

AU - Bartsch, Hauke

AU - Weiner, Michael

AU - Aisen, Paul

AU - Petersen, Ronald

AU - Jack, Clifford R.

AU - Jagust, William

AU - Trojanowki, John Q.

AU - Toga, Arthur W.

AU - Beckett, Laurel

AU - Green, Robert C.

AU - Saykin, Andrew J.

AU - Morris, John

AU - Shaw, Leslie M.

AU - Khachaturian, Zaven

AU - Sorensen, Greg

AU - Carrillo, Maria

AU - Kuller, Lew

AU - Raichle, Marc

AU - Paul, Steven

AU - Davies, Peter

AU - Fillit, Howard

AU - Hefti, Franz

AU - Holtzman, Davie

AU - Mesulman, M. Marcel

AU - Potter, William

AU - Snyder, Peter J.

AU - Schwartz, Adam

AU - Montine, Tom

AU - Thomas, Ronald G.

AU - Donohue, Michael

AU - Walter, Sarah

AU - Gessert, Devon

AU - Sather, Tamie

AU - Jiminez, Gus

AU - Harvey, Danielle

AU - Bernstein, Matthew

AU - Fox, Nick

AU - Thompson, Paul

AU - Schuff, Norbert

AU - DeCarli, Charles

AU - Borowski, Bret

AU - Gunter, Jeff

AU - Senjem, Matt

AU - Vemuri, Prashanthi

AU - Jones, David

AU - Kantarci, Kejal

AU - Ward, Chad

AU - Koeppe, Robert A.

AU - Foster, Norm

AU - Reiman, Eric M.

AU - Chen, Kewei

AU - Mathis, Chet

AU - Landau, Susan

AU - Cairns, Nigel J.

AU - Householder, Erin

AU - Taylor-Reinwald, Lisa

AU - Lee, Virginia M.Y.

AU - Korecka, Magdalena

AU - Figurski, Michal

AU - Crawford, Karen

AU - Neu, Scott

AU - Foroud, Tatiana M.

AU - Potkin, Steven

AU - Shen, Li

AU - Faber, Kelley

AU - Kim, Sungeun

AU - Nho, Kwangsik

AU - Thal, Leon

AU - Frank, Richard

AU - Buckholtz, Neil

AU - Albert, Marilyn

AU - Hsiao, John

N1 - Funding Information: Funded by the National Institute of Mental Health R01MH100351; National Institute on Aging R01AG22381, AG18386 and AG18384; NARSAD Young Investigator award (C.-H.C). Liaison Committee between the Central Norway Regional Health Authority and the Norwegian University of Science and Technology, HUNT administration grants, and National Norwegian Advisory Unit, for functional MRI methods. South East Norway Health Authority (#2013-123), Research Council of Norway (#229129, #213837 and #223273), EU (#602450) and KG Jebsen Foundation. Part of data collection and sharing for this project was funded by the Pediatric Imaging, Neurocognition and Genetics Study (PING), National Institutes of Health Grant RC2DA029475. PING is funded by the National Institute on Drug Abuse and the Eunice Kennedy Shriver National Institute of Child Health & Human Development. PING data are disseminated by the PING Coordinating Center at the Center for Human Development, University of California, San Diego. Part of data collection and sharing for this project was funded by the Alzheimer’s Disease Neuroimaging initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering and through generous contributions from the following: Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd; Janssen Alzheimer Immunotherapy Research & Development, LLC; Johnson & Johnson Pharmaceutical Research & Development LLC; Medpace, Inc.; Merck & Co., Inc.; Meso Scale Diagnostics, LLC; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Synarc Inc.; and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. Publisher Copyright: © 2015 Macmillan Publishers Limited. All rights reserved.

PY - 2015/7/20

Y1 - 2015/7/20

N2 - Little is known about how genetic variation contributes to neuroanatomical variability, and whether particular genomic regions comprising genes or evolutionarily conserved elements are enriched for effects that influence brain morphology. Here, we examine brain imaging and single-nucleotide polymorphisms (SNPs) data from ∼ 2,700 individuals. We show that a substantial proportion of variation in cortical surface area is explained by additive effects of SNPs dispersed throughout the genome, with a larger heritable effect for visual and auditory sensory and insular cortices (h2 ∼ 0.45). Genome-wide SNPs collectively account for, on average, about half of twin heritability across cortical regions (N = 466 twins). We find enriched genetic effects in or near genes. We also observe that SNPs in evolutionarily more conserved regions contributed significantly to the heritability of cortical surface area, particularly, for medial and temporal cortical regions. SNPs in less conserved regions contributed more to occipital and dorsolateral prefrontal cortices.

AB - Little is known about how genetic variation contributes to neuroanatomical variability, and whether particular genomic regions comprising genes or evolutionarily conserved elements are enriched for effects that influence brain morphology. Here, we examine brain imaging and single-nucleotide polymorphisms (SNPs) data from ∼ 2,700 individuals. We show that a substantial proportion of variation in cortical surface area is explained by additive effects of SNPs dispersed throughout the genome, with a larger heritable effect for visual and auditory sensory and insular cortices (h2 ∼ 0.45). Genome-wide SNPs collectively account for, on average, about half of twin heritability across cortical regions (N = 466 twins). We find enriched genetic effects in or near genes. We also observe that SNPs in evolutionarily more conserved regions contributed significantly to the heritability of cortical surface area, particularly, for medial and temporal cortical regions. SNPs in less conserved regions contributed more to occipital and dorsolateral prefrontal cortices.

UR - http://www.scopus.com/inward/record.url?scp=84937413458&partnerID=8YFLogxK

U2 - 10.1038/ncomms8549

DO - 10.1038/ncomms8549

M3 - Article

C2 - 26189703

AN - SCOPUS:84937413458

SN - 2041-1723

VL - 6

JO - Nature communications

JF - Nature communications

M1 - 7549

ER -

Large-scale genomics unveil polygenic architecture of human cortical surface area

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