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1. Hypothesis-driven genome-wide association studies provide novel insights into genetics of reading disabilities

Author: Price, K.M., Wigg, K.G., Eising, E., Feng, Y, Blokland, K., Wilkinson, M., Kerr, E.N., Guger, S.L., Abbondanza, F., Allegrini, A.G., Andlauer, T.F.M., Bates, T.C., Bernard, M., Bonte, M., Boomsma, D.I., Bourgeron, T., Brandeis, D., Carreiras, M., Ceroni, F., Csépe, V., Dale, P.S., DeFries, J.C., Jong, P.F. de, Démonet, J.F., Zeeuw, E.L. de, Franken, M.-C.J., Francks, C., Gerritse, M.L., Gialluisi, A., Gordon, S.D., Gruen, J.R., Hayiou-Thomas, M.E., Hernández-Cabrera, J., Hottenga, J.-J., Hulme, C., Jansen, P.R., Kere, J., Koomar, T., Landerl, K., Leonard, G.T., Liao, Z., Luciano, M., Lyytinen, H., Martin, N.G., Martinelli, A., Maurer, U., Michaelson, J.J., Mirza-Schreiber, N., Moll, K., Monaco, A.P., Morgan, A.T., Müller-Myhsok, B., Newbury, D.F., Nöthen, M.M., Olson, R.K., Paracchini, S., Paus, T., Pausova, Z., Pennell, C.E., Pennington, B.F., Plomin, R.J., Ramus, F., Reilly, S., Richer, L., Rimfeld, K., Schulte-Körne, G., Shapland, C.Y., Simpson, N.H., Smith, S.D., Snowling, M.J., St Pourcain, B., Stein, J.F., Talcott, J.B., Tiemeier, H., Tomblin, J.B., Truong, D.T., Bergen, E. van, Schroeff, M.P. van der, Donkelaar, M.M.J. van, Verhoef, E., Wang, C.A., Watkins, K.E., Whitehouse, A.J.O., Willcutt, E.G., Wright, M.J., Zhu, G., Fisher, S.E., Lovett, M.W., Strug, L.J., Barr, C.L., University of St Andrews. School of Medicine, University of St Andrews. Centre for Biophotonics, University of St Andrews. Biomedical Sciences Research Complex, University of St Andrews. Institute of Behavioural and Neural Sciences, University of St Andrews. St Andrews Bioinformatics Unit, University of St Andrews. Cellular Medicine Division, STEMM - Stem Cells and Metabolism Research Program, Juha Kere / Principal Investigator, Research Programs Unit, University of Helsinki, Consortium, Quantitative Trait Working Group of the GenLang, European Commission, Otorhinolaryngology and Head and Neck Surgery, Child and Adolescent Psychiatry / Psychology, RS: FPN CN 7, Language, Biological Psychology, Amsterdam Reproduction & Development, APH - Mental Health, APH - Methodology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, LEARN! - Educational neuroscience, learning and development, and Human genetics
Subjects: Neuroinformatics, single nucleotide, Candidate gene, Autism Spectrum Disorder, Developmental dyslexia, autism spectrum disorder, QH426 Genetics, Polymorphism, Single Nucleotide, Neuronal migration, 3124 Neurology and psychiatry, polymorphism, Dyslexia, Cellular and Molecular Neuroscience, All institutes and research themes of the Radboud University Medical Center, problem solving, SDG 3 - Good Health and Well-being, dyslexia, Humans, Kiaa0319, Family, humans, Children, QH426, Problem Solving, Biological Psychiatry, MCC, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], genome-wide association study, Dyx1c1, Plasma-membrane, 3rd-DAS, Psychiatry and Mental health, Susceptibility, RC0321, SDG 4 - Quality Education, RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry, Genome-Wide Association Study, Knockout mice
Abstract: Reading Disability (RD) is often characterized by difficulties in the phonology of the language. While the molecular mechanisms underlying it are largely undetermined, loci are being revealed by genome-wide association studies (GWAS). In a previous GWAS for word reading (Price, 2020), we observed that top single-nucleotide polymorphisms (SNPs) were located near to or in genes involved in neuronal migration/axon guidance (NM/AG) or loci implicated in autism spectrum disorder (ASD). A prominent theory of RD etiology posits that it involves disturbed neuronal migration, while potential links between RD-ASD have not been extensively investigated. To improve power to identify associated loci, we up-weighted variants involved in NM/AG or ASD, separately, and performed a new Hypothesis-Driven (HD)–GWAS. The approach was applied to a Toronto RD sample and a meta-analysis of the GenLang Consortium. For the Toronto sample (n = 624), no SNPs reached significance; however, by gene-set analysis, the joint contribution of ASD-related genes passed the threshold (p~1.45 × 10–2, threshold = 2.5 × 10–2). For the GenLang Cohort (n = 26,558), SNPs in DOCK7 and CDH4 showed significant association for the NM/AG hypothesis (sFDR q = 1.02 × 10–2). To make the GenLang dataset more similar to Toronto, we repeated the analysis restricting to samples selected for reading/language deficits (n = 4152). In this GenLang selected subset, we found significant association for a locus intergenic between BTG3-C21orf91 for both hypotheses (sFDR q < 9.00 × 10–4). This study contributes candidate loci to the genetics of word reading. Data also suggest that, although different variants may be involved, alleles implicated in ASD risk may be found in the same genes as those implicated in word reading. This finding is limited to the Toronto sample suggesting that ascertainment influences genetic associations., Translational Psychiatry, 12 (1), ISSN:2158-3188
Published: 2022

2. Genome-wide analyses of individual differences in quantitatively assessed reading- and language-related skills in up to 34,000 people

Author: Eising, E., Mirza-Schreiber, N., Zeeuw, E.L. de, Wang, C.A., Truong, D.T., Allegrini, A.G., Shapland, C.Y., Zhu, G., Wigg, K.G., Gerritse, M.L., Molz, B., Alagöz, G., Gialluisi, A., Abbondanza, F., Rimfeld, K., Donkelaar, M.M.J. van, Liao, Z., Jansen, P.R., Andlauer, T.F.M., Bates, T.C., Bernard, M., Blokland, K., Bonte, M., Børglum, A.D., Bourgeron, T., Brandeis, D., Ceroni, F., Csépe, V., Dale, P.S., Jong, P.F. de, DeFries, J.C., Démonet, J.F., Demontis, D., Feng, Yu, Gordon, S.D.S., Guger, S.L., Hayiou-Thomas, M.E., Hernández-Cabrera, J.A., Hottenga, J.J., Hulme, C., Kere, J., Kerr, E.N., Koomar, T., Landerl, K., Leonard, G.T., Lovett, M.W., Lyytinen, H., Martin, N.G., Martinelli, A., Maurer, U., Michaelson, J.J., Moll, K., Monaco, A.P., Morgan, A.T., Nöthen, M.M., Pausova, Z., Pennell, C.E., Pennington, B.F., Price, K.M., Rajagopal, V.M., Ramus, F., Richer, L., Simpson, N.H., Smith, S.D., Snowling, M.J., Stein, J., Strug, L.J., Talcott, J.B., Tiemeier, H., Schroeff, M.P. van der, Verhoef, E., Watkins, K.E., Wilkinson, M., Wright, M.J., Barr, C.L., Boomsma, D.I., Carreiras, M., Franken, M.J., Gruen, J.R., Luciano, M., Müller-Myhsok, B., Newbury, D.F., Olson, R.K., Paracchini, S., Paus, T., Plomin, R., Reilly, S., Schulte-Körne, G., Tomblin, J.B., Bergen, E. van, Whitehouse, A.J.O., Willcutt, E.G., Pourcain, B. St, Francks, C., Fisher, S.E., St Pourcain, B., Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Laboratoire de sciences cognitives et psycholinguistique (LSCP), Département d'Etudes Cognitives - ENS Paris (DEC), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École des hautes études en sciences sociales (EHESS)-Centre National de la Recherche Scientifique (CNRS), Human genetics, APH - Aging & Later Life, APH - Mental Health, Biological Psychology, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Amsterdam Reproduction & Development, APH - Methodology, LEARN! - Educational neuroscience, learning and development, Child and Adolescent Psychiatry / Psychology, Otorhinolaryngology and Head and Neck Surgery, STEMM - Stem Cells and Metabolism Research Program, Juha Kere / Principal Investigator, Research Programs Unit, University of Helsinki, Language, RS: FPN CN 7, The Royal Society, University of St Andrews. Cellular Medicine Division, University of St Andrews. School of Medicine, University of St Andrews. Centre for Biophotonics, University of St Andrews. Biomedical Sciences Research Complex, University of St Andrews. Institute of Behavioural and Neural Sciences, and University of St Andrews. St Andrews Bioinformatics Unit
Subjects: Neuroinformatics, Adult, kieli ja kielet, Adolescent, Individuality, QH426 Genetics, Polymorphism, Single Nucleotide, lukeminen, Language in Interaction, Young Adult, SDG 3 - Good Health and Well-being, RA0421, reading, RA0421 Public health. Hygiene. Preventive Medicine, Humans, Speech, study, Polymorphism, Reading j, Preschool, Child, QH426, perinnöllisyys, Genome-wide Association Study, Language, Meta-analysis, Reading, MCC, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], genome-wide association study, language, Multidisciplinary, meta-analyysi, 1184 Genetics, developmental biology, physiology, kielitaito, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, DAS, Single Nucleotide, meta-analysis, Genetic Loci, Child, Preschool, Genome-Wide Association Study, perimä, lukutaito, genome-wide association, SDG 4 - Quality Education
Abstract: Published August 23, 2022 The use of spoken and written language is a fundamental human capacity. Individual differences in reading- and language-related skills are influenced by genetic variation, with twin-based heritability estimates of 30 to 80% depending on the trait. The genetic architecture is complex, heterogeneous, and multifactorial, but investigations of contributions of single-nucleotide polymorphisms (SNPs) were thus far underpowered. We present a multicohort genome-wide association study (GWAS) of five traits assessed individually using psychometric measures (word reading, nonword reading, spelling, phoneme awareness, and nonword repetition) in samples of 13,633 to 33,959 participants aged 5 to 26 y. We identified genome-wide significant association with word reading (rs11208009, P = 1.098 × 1028) at a locus that has not been associated with intelligence or educational attainment. All five reading-/language-related traits showed robust SNP heritability, accounting for 13 to 26% of trait variability. Genomic structural equation modeling revealed a shared genetic factor explaining most of the variation in word/nonword reading, spelling, and phoneme awareness, which only partially overlapped with genetic variation contributing to nonword repetition, intelligence, and educational attainment. A multivariate GWAS of word/nonword reading, spelling, and phoneme awareness maximized power for follow-up investigation. Genetic correlation analysis with neuroimaging traits identified an association with the surface area of the banks of the left superior temporal sulcus, a brain region linked to the processing of spoken and written language. Heritability was enriched for genomic elements regulating gene expression in the fetal brain and in chromosomal regions that are depleted of Neanderthal variants. Together, these results provide avenues for deciphering the biological underpinnings of uniquely human traits. We thank all the children, twins, families, and participants who took part and are taking part in the 22 cohorts whose data contributed to these GWAS meta-analyses; the staff working on the different cohorts, including volunteers, study coordinators, interviewers, teachers, nurses, research scientists, general practitioners, midwives, psychologists, psychometrists, computer and laboratory technicians, and colleagues who assisted in the quality control and preparation of the imputed GWAS data; and the pharmacies and hospitals that were involved. B.M., B.M.-M., B.S.P., C.F., E.E., E.V., G.A., M.v.D., and S.E.F. are supported by the Max Planck Society. A.G. and T.F.M.A. were supported by the Munich Cluster for Systems Neurology (SyNergy), and A.G. was supported by Fondazione Umberto Veronesi. A.T.M. is supported by National Health and Medical Research Council of Australia (NHMRC) Grants 1105008 and 1195955 and Centre of Research Excellence Grant 1116976. A.J.O.W. is supported by NHMRC Grant 1173896. B.S.P. is supported by Simons Foundation Autism Research Initiative Grant 514787. C.Y.S. works in the Medical Research Council Integrative Epidemiology Unit at the University of Bristol (MC_UU_00011/3). D.I.B. acknowledges Royal Netherlands Academy of Science Professor Award PAH/6635. E.E. is supported by NIH Grant R01DC016977. E.G.W. and J.R.G. are supported by National Institute of Child Health and Human Development (NICHD) Grant P50 HD 27802. F.R. is supported by Agence Nationale de la Recherche Grants ANR-06-NEURO-019-01, ANR-17-EURE-0017 IEC, ANR-10-IDEX-0001-02 PSL, and ANR-11-BSV4-014-01 and European Commission Grant LSHM-CT-2005-018696. H.T. is supported by the Netherlands Organization for Scientific Research (NWO) and Netherlands Organisation for Health Research and Development (ZonMW) Grant VICI 016.VICI.170.200. J.C.D. was supported by NICHD Grant P50 HD 27802. J.J.M., J.B.To., and T.K. were supported by NIH Grant R01 DC014489. K.M.P. was supported by the Hospital for Sick Children Research Training Program (Restracomp). K.R. is supported by a Sir Henry Wellcome Postdoctoral Fellowship (213514/Z/18/Z). M.J.S. is supported by Wellcome Trust Grant WT082032MA. S.P. and F.A. are supported by Royal Society Grants UF150663 and RGF\EA\180141. T.B. is supported by Institut Pasteur, the Bettencourt-Schueller Foundation, and Université de Paris. The Adolescent Brain Cognitive Development Study is supported by the NIH and additional federal partners (NIH Grants U01DA041048, U01DA050989, U01DA051016, U01DA041022, U01DA051018, U01DA051037, U01DA050987, U01DA041174, U01DA041106, U01DA041117, U01DA041028, U01DA041134, U01DA050988, U01DA051039, U01DA041156, U01DA041025, U01DA041120, U01DA051038, U01DA041148, U01DA041093, U01DA041089, U24DA041123, and U24DA041147). The Aston Cohort was supported by funding from European Union (EU) Horizon 2020 Programme 641652 and Waterloo Foundation Grant 797/17290. The St. Andrews Bioinformatics Unit is funded by Wellcome Trust Grants 105621/Z/14/Z and 204821/Z/16/Z. ALSPAC is supported by UK Medical Research Council and Wellcome Grant 217065/Z/19/Z and the University of Bristol. A comprehensive list of grant funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). The Basque Center on Cognition, Brain and Language (BCBL) cohort was supported by the Basque Government through the Basic Excellence Research Centre program and the Agencia Estatal de Investigación through BCBL Severo Ochoa excellence accreditation. The Brisbane Adolescent Twin Sample was supported by Australian Research Council Grants A7960034, A79906588, A79801419, DP0212016, and DP0343921, with genotyping funded by the NHMRC Grant 389891. The Colorado Learning Disabilities Research Center cohort was supported by NICHD Grant P50 HD 27802. The Early Language in Victoria Study was supported by NHMRC Grant 436958. The Familial Influences on Literacy Abilities cohort is supported by the University of Amsterdam, the Max Planck Institue Nijmegen, and NWO Grants Rubicon 446-12-005 and VENI 451-15-017. The GRaD study was funded by the Manton Foundation, NIH Grants P50-HD027802 and K99-HD094902, and the Lambert Family. NeuroDys was funded by an EU Sixth Framework Program grant to the NeuroDys Consortium, Swiss National Science Foundation Grant 32-108130, and Austrian Science Fund Grant 18351-B02. The Netherlands Twin Register is funded by NWO Grants 480-04-004, 481-08-011, 056-32-010, 024.001.003, 480-15-001/674, 184.021.007, 184.033.111, and 56-464-14192; ZonMW Grants 911-09-032 and 912-10-020; the Amsterdam Public Health and Amsterdam Reproduction and Development Research Institutes; European Science Council Grant ERC Advanced 230374; EU Seventh Framework Program (FP7) Grant FP7/2007-2013: 602768; National Institute of Mental Health (NIMH) Grants U24 MH068457-06, R01 MH58799-03, and 1RC2 MH089995; and the Avera Institute for Human Genetics. The Pediatric Imaging, Neurocognition, and Genetics cohort is funded by NIH Grant RC2DA029475, the National Institute on Drug Abuse, and the Eunice Kennedy Shriver NICHD. The Philadelphia Neurodevelopmental Cohort is funded by NIH Grants RC2MH089983 and RC2MH089924, an institutional development award to the Center for Applied Genomics from The Children’s Hospital of Philadelphia, and a donation from Adele and Daniel Kubert and thanks the NIH data repository. The Raine study was supported by long-term funding from NHMRC Grants 572613, 403981, and 1059711 and Canadian Institutes of Health Research (CIHR) Grant MOP-82893. Funding was also provided by the University of Western Australia, Curtin University, the Women and Infants Research Foundation, the Telethon Kids Institute, Edith Cowan University, Murdoch University, the University of Notre Dame Australia, and the Raine Medical Research Foundation. The Raine study analyses were supported by the Pawsey Supercomputing Centre with funding from the Australian Government and the Government of Western Australia. The Saguenay Youth Study is supported by the CIHR, the Heart and Stroke Foundation of Quebec, and the Canadian Foundation for Innovation. The SLI Consortium was funded by Wellcome Trust Grant 076566 and UK Medical Research Council Grant G1000569. The Twins Early Development Study is supported by UK Medical Research Council Grants MR/V012878/1 and MR/M021475/1, NIH Grant AG046938, and the EU FP7 grant FP7/2007-2013/: 602768. Toronto was supported by CIHR Grant MOP-133440. UK Dyslexia was supported by Wellcome Trust Grants 076566/Z/05/Z and 075491/Z/04, Waterloo Foundation Grant 797–1720, EU Grant 018696, and Royal Society Grant UF100463. The York cohort was funded by Wellcome Trust Grant 082036/B/07/Z. We acknowledge iPSYCH for sharing their summary statistics. The iPSYCH team was supported by Lundbeck Foundation Grants R102-A9118, R155-2014-1724, and R248-2017-2003; NIMH Grant 1U01MH109514-01; and the Universities and University Hospitals of Aarhus and Copenhagen. The Danish National Biobank resource was supported by the Novo Nordisk Foundation. High-performance computer capacity was provided by the Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing, Aarhus University, Denmark.
Published: 2022

3. Genome-wide analyses of individual differences in quantitatively assessed reading- and language-related skills in up to 34,000 people

Author: Eising, E, Mirza-Schreiber, N, de Zeeuw, EL, Wang, CA, Truong, DT, Allegrini, AG, Shapland, CY, Zhu, G, Wigg, KG, Gerritse, ML, Molz, B, Alagoz, G, Gialluisi, A, Abbondanza, F, Rimfeld, K, van Donkelaar, M, Liao, Z, Jansen, PR, Andlauer, TFM, Bates, TC, Bernard, M, Blokland, K, Bonte, M, Borglum, AD, Bourgeron, T, Brandeis, D, Ceronihh, F, Csepe, V, Dale, PS, de Jong, PF, DeFries, JC, Demonet, J-F, Demontis, D, Feng, Y, Gordon, SD, Guger, SL, Hayiou-Thomas, ME, Hernandez-Cabrera, JA, Hottenga, J-J, Hulme, C, Kere, J, Kerr, EN, Koomar, T, Landerl, K, Leonard, GT, Lovett, MW, Lyytinen, H, Martin, NG, Martinelli, A, Maurer, U, Michaelson, JJ, Moll, K, Monaco, AP, Morgan, AT, Nothen, MM, Pausova, Z, Pennell, CE, Pennington, BF, Price, KM, Rajagopal, VM, Ramus, F, Richer, L, Simpson, NH, Smith, SD, Snowling, MJ, Stein, J, Struguuu, LJ, Talcott, JB, Tiemeier, H, van der Schroeff, MP, Verhoef, E, Watkins, KE, Wilkinson, M, Wright, MJ, Barr, CL, Boomsma, D, Carreiras, M, Franken, M-CJ, Gruen, JR, Luciano, M, Muller-Myhsok, B, Newbury, DF, Olson, RK, Paracchini, S, Paus, T, Plomin, R, Reilly, S, Schulte-Korn, G, Tomblin, JB, Bergen, E, Whitehouse, AJO, Willcutt, EG, St Pourcain, B, Francks, C, Fisher, SE, Eising, E, Mirza-Schreiber, N, de Zeeuw, EL, Wang, CA, Truong, DT, Allegrini, AG, Shapland, CY, Zhu, G, Wigg, KG, Gerritse, ML, Molz, B, Alagoz, G, Gialluisi, A, Abbondanza, F, Rimfeld, K, van Donkelaar, M, Liao, Z, Jansen, PR, Andlauer, TFM, Bates, TC, Bernard, M, Blokland, K, Bonte, M, Borglum, AD, Bourgeron, T, Brandeis, D, Ceronihh, F, Csepe, V, Dale, PS, de Jong, PF, DeFries, JC, Demonet, J-F, Demontis, D, Feng, Y, Gordon, SD, Guger, SL, Hayiou-Thomas, ME, Hernandez-Cabrera, JA, Hottenga, J-J, Hulme, C, Kere, J, Kerr, EN, Koomar, T, Landerl, K, Leonard, GT, Lovett, MW, Lyytinen, H, Martin, NG, Martinelli, A, Maurer, U, Michaelson, JJ, Moll, K, Monaco, AP, Morgan, AT, Nothen, MM, Pausova, Z, Pennell, CE, Pennington, BF, Price, KM, Rajagopal, VM, Ramus, F, Richer, L, Simpson, NH, Smith, SD, Snowling, MJ, Stein, J, Struguuu, LJ, Talcott, JB, Tiemeier, H, van der Schroeff, MP, Verhoef, E, Watkins, KE, Wilkinson, M, Wright, MJ, Barr, CL, Boomsma, D, Carreiras, M, Franken, M-CJ, Gruen, JR, Luciano, M, Muller-Myhsok, B, Newbury, DF, Olson, RK, Paracchini, S, Paus, T, Plomin, R, Reilly, S, Schulte-Korn, G, Tomblin, JB, Bergen, E, Whitehouse, AJO, Willcutt, EG, St Pourcain, B, Francks, C, and Fisher, SE
Abstract: The use of spoken and written language is a fundamental human capacity. Individual differences in reading- and language-related skills are influenced by genetic variation, with twin-based heritability estimates of 30 to 80% depending on the trait. The genetic architecture is complex, heterogeneous, and multifactorial, but investigations of contributions of single-nucleotide polymorphisms (SNPs) were thus far underpowered. We present a multicohort genome-wide association study (GWAS) of five traits assessed individually using psychometric measures (word reading, nonword reading, spelling, phoneme awareness, and nonword repetition) in samples of 13,633 to 33,959 participants aged 5 to 26 y. We identified genome-wide significant association with word reading (rs11208009, P = 1.098 × 10-8) at a locus that has not been associated with intelligence or educational attainment. All five reading-/language-related traits showed robust SNP heritability, accounting for 13 to 26% of trait variability. Genomic structural equation modeling revealed a shared genetic factor explaining most of the variation in word/nonword reading, spelling, and phoneme awareness, which only partially overlapped with genetic variation contributing to nonword repetition, intelligence, and educational attainment. A multivariate GWAS of word/nonword reading, spelling, and phoneme awareness maximized power for follow-up investigation. Genetic correlation analysis with neuroimaging traits identified an association with the surface area of the banks of the left superior temporal sulcus, a brain region linked to the processing of spoken and written language. Heritability was enriched for genomic elements regulating gene expression in the fetal brain and in chromosomal regions that are depleted of Neanderthal variants. Together, these results provide avenues for deciphering the biological underpinnings of uniquely human traits.
Published: 2022

4. Hypothesis-driven genome-wide association studies provide novel insights into genetics of reading disabilities

Author: Price, KM, Wigg, KG, Eising, E, Feng, Y, Blokland, K, Wilkinson, M, Kerr, EN, Guger, SL, Abbondanza, F, Allegrini, AG, Andlauer, TFM, Bates, TC, Bernard, M, Bonte, M, Boomsma, DI, Bourgeron, T, Brandeis, D, Carreiras, M, Ceroni, F, Csepe, V, Dale, PS, DeFries, JC, de Jong, PF, Demonet, JF, de Zeeuw, EL, Franken, M-CJ, Francks, C, Gerritse, M, Gialluisi, A, Gordon, SD, Gruen, JR, Hayiou-Thomas, ME, Hernandez-Cabrera, J, Hottenga, J-J, Hulme, C, Jansen, PR, Kere, J, Koomar, T, Landerl, K, Leonard, GT, Liao, Z, Luciano, M, Lyytinen, H, Martin, NG, Martinelli, A, Maurer, U, Michaelson, JJ, Mirza-Schreiber, N, Moll, K, Monaco, AP, Morgan, AT, Mueller-Myhsok, B, Newbury, DF, Noethen, MM, Olson, RK, Paracchini, S, Paus, T, Pausova, Z, Pennell, CE, Pennington, BF, Plomin, RJ, Ramus, F, Reilly, S, Richer, L, Rimfeld, K, Schulte-Korne, G, Shapland, CY, Simpson, NH, Smith, SD, Snowling, MJ, St Pourcain, B, Stein, JF, Talcott, JB, Tiemeier, H, Tomblin, JB, Truong, DT, van Bergen, E, van der Schroeff, MP, Van Donkelaar, M, Verhoef, E, Wang, CA, Watkins, KE, Whitehouse, AJO, Willcutt, EG, Wright, MJ, Zhu, G, Fisher, SE, Lovett, MW, Strug, LJ, Barr, CL, Price, KM, Wigg, KG, Eising, E, Feng, Y, Blokland, K, Wilkinson, M, Kerr, EN, Guger, SL, Abbondanza, F, Allegrini, AG, Andlauer, TFM, Bates, TC, Bernard, M, Bonte, M, Boomsma, DI, Bourgeron, T, Brandeis, D, Carreiras, M, Ceroni, F, Csepe, V, Dale, PS, DeFries, JC, de Jong, PF, Demonet, JF, de Zeeuw, EL, Franken, M-CJ, Francks, C, Gerritse, M, Gialluisi, A, Gordon, SD, Gruen, JR, Hayiou-Thomas, ME, Hernandez-Cabrera, J, Hottenga, J-J, Hulme, C, Jansen, PR, Kere, J, Koomar, T, Landerl, K, Leonard, GT, Liao, Z, Luciano, M, Lyytinen, H, Martin, NG, Martinelli, A, Maurer, U, Michaelson, JJ, Mirza-Schreiber, N, Moll, K, Monaco, AP, Morgan, AT, Mueller-Myhsok, B, Newbury, DF, Noethen, MM, Olson, RK, Paracchini, S, Paus, T, Pausova, Z, Pennell, CE, Pennington, BF, Plomin, RJ, Ramus, F, Reilly, S, Richer, L, Rimfeld, K, Schulte-Korne, G, Shapland, CY, Simpson, NH, Smith, SD, Snowling, MJ, St Pourcain, B, Stein, JF, Talcott, JB, Tiemeier, H, Tomblin, JB, Truong, DT, van Bergen, E, van der Schroeff, MP, Van Donkelaar, M, Verhoef, E, Wang, CA, Watkins, KE, Whitehouse, AJO, Willcutt, EG, Wright, MJ, Zhu, G, Fisher, SE, Lovett, MW, Strug, LJ, and Barr, CL
Abstract: Reading Disability (RD) is often characterized by difficulties in the phonology of the language. While the molecular mechanisms underlying it are largely undetermined, loci are being revealed by genome-wide association studies (GWAS). In a previous GWAS for word reading (Price, 2020), we observed that top single-nucleotide polymorphisms (SNPs) were located near to or in genes involved in neuronal migration/axon guidance (NM/AG) or loci implicated in autism spectrum disorder (ASD). A prominent theory of RD etiology posits that it involves disturbed neuronal migration, while potential links between RD-ASD have not been extensively investigated. To improve power to identify associated loci, we up-weighted variants involved in NM/AG or ASD, separately, and performed a new Hypothesis-Driven (HD)-GWAS. The approach was applied to a Toronto RD sample and a meta-analysis of the GenLang Consortium. For the Toronto sample (n = 624), no SNPs reached significance; however, by gene-set analysis, the joint contribution of ASD-related genes passed the threshold (p~1.45 × 10-2, threshold = 2.5 × 10-2). For the GenLang Cohort (n = 26,558), SNPs in DOCK7 and CDH4 showed significant association for the NM/AG hypothesis (sFDR q = 1.02 × 10-2). To make the GenLang dataset more similar to Toronto, we repeated the analysis restricting to samples selected for reading/language deficits (n = 4152). In this GenLang selected subset, we found significant association for a locus intergenic between BTG3-C21orf91 for both hypotheses (sFDR q < 9.00 × 10-4). This study contributes candidate loci to the genetics of word reading. Data also suggest that, although different variants may be involved, alleles implicated in ASD risk may be found in the same genes as those implicated in word reading. This finding is limited to the Toronto sample suggesting that ascertainment influences genetic associations.
Published: 2022

5. Genome-wide association study reveals new insights into the heritability and genetic correlates of developmental dyslexia

Author: Gialluisi, A., Andlauer, T.F.M., Mirza-Schreiber, N., Moll, K., Becker, J., Hoffmann, P., Fisher, S.E., Mueller-Myhsok, B., Schulte-Koerne, G., St Pourcain, B., Francks, C., Gialluisi, A., Andlauer, T.F.M., Mirza-Schreiber, N., Moll, K., Becker, J., Hoffmann, P., Fisher, S.E., Mueller-Myhsok, B., Schulte-Koerne, G., St Pourcain, B., and Francks, C.
Abstract: 06 november 2020, Contains fulltext : 247012.pdf (Publisher’s version ) (Open Access)
Published: 2021

6. The genetic architecture of the human cerebral cortex

Author: Grasby, K.L., Jahanshad, N., Painter, J.N., Colodro-Conde, L., Bralten, J., Hibar, D.P., Lind, P.A., Pizzagalli, F., Ching, C.R.K., McMahon, M.A.B., Shatokhina, N., Zsembik, L.C.P., Thomopoulos, S.I., Zhu, A.H., Strike, L.T., Agartz, I., Alhusaini, S., Almeida, M.A.A., Alnæs, D., Amlien, I.K., Andersson, M., Ard, T., Armstrong, N.J., Ashley-Koch, A., Atkins, J.R., Bernard, M., Brouwer, R.M., Buimer, E.E.L., Bülow, R., Bürger, C., Cannon, D.M., Chakravarty, M.M., Chen, Q., Cheung, J.W., Couvy-Duchesne, B., Dale, A.M., Dalvie, S., de Araujo, T.K., de Zubicaray, G.I., de Zwarte, S.M.C., den Braber, A., Doan, N.T., Dohm, K., Ehrlich, S., Engelbrecht, H-R, Erk, S., Fan, C.C., Fedko, I.O., Foley, S.F., Ford, J.M., Fukunaga, M., Garrett, M.E., Ge, T., Giddaluru, S., Goldman, A.L., Green, M.J., Groenewold, N.A., Grotegerd, D., Gurholt, T.P., Gutman, B.A., Hansell, N.K., Harris, M.A., Harrison, M.B., Haswell, C.C., Hauser, M., Herms, S., Heslenfeld, D.J., Ho, N.F., Hoehn, D., Hoffmann, P., Holleran, L., Hoogman, M., Hottenga, J-J, Ikeda, M., Janowitz, D., Jansen, I.E., Jia, T., Jockwitz, C., Kanai, R., Karama, S., Kasperaviciute, D., Kaufmann, T., Kelly, S., Kikuchi, M., Klein, M., Knapp, M., Knodt, A.R., Krämer, B., Lam, M., Lancaster, T.M., Lee, P.H., Lett, T.A., Lewis, L.B., Lopes-Cendes, I., Luciano, M., Macciardi, F., Marquand, A.F., Mathias, S.R., Melzer, T.R., Milaneschi, Y., Mirza-Schreiber, N., Moreira, J.C.V., Mühleisen, T.W., Müller-Myhsok, B., Najt, P., Nakahara, S., Nho, K., Olde Loohuis, L.M., Orfanos, D.P., Pearson, J.F., Pitcher, T.L., Pütz, B., Quidé, Y., Ragothaman, A., Rashid, F.M., Reay, W.R., Redlich, R., Reinbold, C.S., Repple, J., Richard, G., Riedel, B.C., Risacher, S.L., Rocha, C.S., Mota, N.R., Salminen, L., Saremi, A., Saykin, A.J., Schlag, F., Schmaal, L., Schofield, P.R., Secolin, R., Shapland, C.Y., Shen, L., Shin, J., Shumskaya, E., Sønderby, I.E., Sprooten, E., Tansey, K.E., Teumer, A., Thalamuthu, A., Tordesillas-Gutierrez, D., Turner, J.A., Uhlmann, A., Vallerga, C.L., van der Meer, D., van Donkelaar, M.M.J., van Eijk, L., Van Erp, T.G.M., van Haren, N.E.M., Van Rooij, D., van Tol, M-J, Veldink, J.H., Verhoef, E., Walton, E., Wang, M., Wang, Y., Wardlaw, J.M., Wen, W., Westlye, L.T., Whelan, C.D., Witt, S.H., Wittfeld, K., Wolf, C., Wolfers, T., Wu, J.Q., Yasuda, C.L., Zaremba, D., Zhang, Z., Zwiers, M.P., Artiges, E., Assareh, A.A., Ayesa-Arriola, R., Belger, A., Brandt, C.L., Brown, G.G., Cichon, S., Curran, J.E., Davies, G.E., Degenhardt, F., Dennis, M.F., Dietsche, B., Djurovic, S., Doherty, C.P., Espiritu, R., Garijo, D., Gil, Y., Gowland, P.A., Green, R.C., Häusler, A.N., Heindel, W., Ho, B-C., Hoffmann, W.U., Holsboer, F., Homuth, G., Hosten, N., Jack, C.R., Jang, M., Jansen, A., Kimbrel, N.A., Kolskår, K., Koops, S., Krug, A., Lim, K.O., Luykx, J.J., Mathalon, D.H., Mather, K.A., Mattay, V.S., Matthews, S., Mayoral Van Son, J., McEwen, S.C., Melle, I., Morris, D.W., Mueller, B.A., Nauck, M., Nordvik, J.E., Nöthen, M.M., O’Leary, D.S., Opel, N., Martinot, M-L.P., Pike, G.B., Preda, A., Quinlan, E.B., Rasser, P.E., Ratnakar, V., Reppermund, S., Steen, V.M., Tooney, P.A., Torres, F.R., Veltman, D.J., Voyvodic, J.T., Whelan, R., White, T., Yamamori, H., Adams, H.H.H., Bis, J.C., Debette, S., DeCarli, C., Fornage, M., Gudnason, V., Hofer, E., Ikram, M.A., Launer, L., Longstreth, W.T., Lopez, O.L., Mazoyer, B., Mosley, T.H., Roshchupkin, G.V., Satizabal, C.L., Schmidt, R., Seshadri, S., Yang, Q., Alvim, M.K.M., Ames, D., Anderson, T.J., Andreassen, O.A., Arias-Vasquez, A., Bastin, M.E., Baune, B.T., Beckham, J.C., Blangero, J., Boomsma, D.I., Brodaty, H., Brunner, H.G., Buckner, R.L., Buitelaar, J.K., Bustillo, J.R., Cahn, W., Cairns, M.J., Calhoun, V., Carr, V.J., Caseras, X., Caspers, S., Cavalleri, G.L., Cendes, F., Corvin, A., Crespo-Facorro, B., Dalrymple-Alford, J.C., Dannlowski, U., de Geus, E.J.C., Deary, I.J., Delanty, N., Depondt, C., Desrivières, S., Donohoe, G., Espeseth, T., Fernández, G., Fisher, S.E., Flor, H., Forstner, A.J., Francks, C., Franke, B., Glahn, D.C., Gollub, R.L., Grabe, H.J., Gruber, O., Håberg, A.K., Hariri, A.R., Hartman, C.A., Hashimoto, R., Heinz, A., Henskens, F.A., Hillegers, M.H.J., Hoekstra, P.J., Holmes, A.J., Hong, L.E., Hopkins, W.D., Hulshoff Pol, H.E., Jernigan, T.L., Jönsson, E.G., Kahn, R.S., Kennedy, M.A., Kircher, T.T.J., Kochunov, P., Kwok, J.B.J., Le Hellard, S., Loughland, C.M., Martin, N.G., Martinot, J-L, McDonald, C., McMahon, K.L., Meyer-Lindenberg, A., Michie, P.T., Morey, R.A., Mowry, B., Nyberg, L., Oosterlaan, J., Ophoff, R.A., Pantelis, C., Paus, T., Pausova, Z., Penninx, B.W.J.H., Polderman, T.J.C., Posthuma, D., Rietschel, M., Roffman, J.L., Rowland, L.M., Sachdev, P.S., Sämann, P.G., Schall, U., Schumann, G., Scott, R.J., Sim, K., Sisodiya, S.M., Smoller, J.W., Sommer, I.E., St Pourcain, B., Stein, D.J., Toga, A.W., Trollor, J.N., van der Wee, N.J.A., van ’t Ent, D., Völzke, H., Walter, H., Weber, B., Weinberger, D.R., Wright, M.J., Zhou, J., Stein, J.L., Thompson, P.M., Medland, S.E., Grasby, K.L., Jahanshad, N., Painter, J.N., Colodro-Conde, L., Bralten, J., Hibar, D.P., Lind, P.A., Pizzagalli, F., Ching, C.R.K., McMahon, M.A.B., Shatokhina, N., Zsembik, L.C.P., Thomopoulos, S.I., Zhu, A.H., Strike, L.T., Agartz, I., Alhusaini, S., Almeida, M.A.A., Alnæs, D., Amlien, I.K., Andersson, M., Ard, T., Armstrong, N.J., Ashley-Koch, A., Atkins, J.R., Bernard, M., Brouwer, R.M., Buimer, E.E.L., Bülow, R., Bürger, C., Cannon, D.M., Chakravarty, M.M., Chen, Q., Cheung, J.W., Couvy-Duchesne, B., Dale, A.M., Dalvie, S., de Araujo, T.K., de Zubicaray, G.I., de Zwarte, S.M.C., den Braber, A., Doan, N.T., Dohm, K., Ehrlich, S., Engelbrecht, H-R, Erk, S., Fan, C.C., Fedko, I.O., Foley, S.F., Ford, J.M., Fukunaga, M., Garrett, M.E., Ge, T., Giddaluru, S., Goldman, A.L., Green, M.J., Groenewold, N.A., Grotegerd, D., Gurholt, T.P., Gutman, B.A., Hansell, N.K., Harris, M.A., Harrison, M.B., Haswell, C.C., Hauser, M., Herms, S., Heslenfeld, D.J., Ho, N.F., Hoehn, D., Hoffmann, P., Holleran, L., Hoogman, M., Hottenga, J-J, Ikeda, M., Janowitz, D., Jansen, I.E., Jia, T., Jockwitz, C., Kanai, R., Karama, S., Kasperaviciute, D., Kaufmann, T., Kelly, S., Kikuchi, M., Klein, M., Knapp, M., Knodt, A.R., Krämer, B., Lam, M., Lancaster, T.M., Lee, P.H., Lett, T.A., Lewis, L.B., Lopes-Cendes, I., Luciano, M., Macciardi, F., Marquand, A.F., Mathias, S.R., Melzer, T.R., Milaneschi, Y., Mirza-Schreiber, N., Moreira, J.C.V., Mühleisen, T.W., Müller-Myhsok, B., Najt, P., Nakahara, S., Nho, K., Olde Loohuis, L.M., Orfanos, D.P., Pearson, J.F., Pitcher, T.L., Pütz, B., Quidé, Y., Ragothaman, A., Rashid, F.M., Reay, W.R., Redlich, R., Reinbold, C.S., Repple, J., Richard, G., Riedel, B.C., Risacher, S.L., Rocha, C.S., Mota, N.R., Salminen, L., Saremi, A., Saykin, A.J., Schlag, F., Schmaal, L., Schofield, P.R., Secolin, R., Shapland, C.Y., Shen, L., Shin, J., Shumskaya, E., Sønderby, I.E., Sprooten, E., Tansey, K.E., Teumer, A., Thalamuthu, A., Tordesillas-Gutierrez, D., Turner, J.A., Uhlmann, A., Vallerga, C.L., van der Meer, D., van Donkelaar, M.M.J., van Eijk, L., Van Erp, T.G.M., van Haren, N.E.M., Van Rooij, D., van Tol, M-J, Veldink, J.H., Verhoef, E., Walton, E., Wang, M., Wang, Y., Wardlaw, J.M., Wen, W., Westlye, L.T., Whelan, C.D., Witt, S.H., Wittfeld, K., Wolf, C., Wolfers, T., Wu, J.Q., Yasuda, C.L., Zaremba, D., Zhang, Z., Zwiers, M.P., Artiges, E., Assareh, A.A., Ayesa-Arriola, R., Belger, A., Brandt, C.L., Brown, G.G., Cichon, S., Curran, J.E., Davies, G.E., Degenhardt, F., Dennis, M.F., Dietsche, B., Djurovic, S., Doherty, C.P., Espiritu, R., Garijo, D., Gil, Y., Gowland, P.A., Green, R.C., Häusler, A.N., Heindel, W., Ho, B-C., Hoffmann, W.U., Holsboer, F., Homuth, G., Hosten, N., Jack, C.R., Jang, M., Jansen, A., Kimbrel, N.A., Kolskår, K., Koops, S., Krug, A., Lim, K.O., Luykx, J.J., Mathalon, D.H., Mather, K.A., Mattay, V.S., Matthews, S., Mayoral Van Son, J., McEwen, S.C., Melle, I., Morris, D.W., Mueller, B.A., Nauck, M., Nordvik, J.E., Nöthen, M.M., O’Leary, D.S., Opel, N., Martinot, M-L.P., Pike, G.B., Preda, A., Quinlan, E.B., Rasser, P.E., Ratnakar, V., Reppermund, S., Steen, V.M., Tooney, P.A., Torres, F.R., Veltman, D.J., Voyvodic, J.T., Whelan, R., White, T., Yamamori, H., Adams, H.H.H., Bis, J.C., Debette, S., DeCarli, C., Fornage, M., Gudnason, V., Hofer, E., Ikram, M.A., Launer, L., Longstreth, W.T., Lopez, O.L., Mazoyer, B., Mosley, T.H., Roshchupkin, G.V., Satizabal, C.L., Schmidt, R., Seshadri, S., Yang, Q., Alvim, M.K.M., Ames, D., Anderson, T.J., Andreassen, O.A., Arias-Vasquez, A., Bastin, M.E., Baune, B.T., Beckham, J.C., Blangero, J., Boomsma, D.I., Brodaty, H., Brunner, H.G., Buckner, R.L., Buitelaar, J.K., Bustillo, J.R., Cahn, W., Cairns, M.J., Calhoun, V., Carr, V.J., Caseras, X., Caspers, S., Cavalleri, G.L., Cendes, F., Corvin, A., Crespo-Facorro, B., Dalrymple-Alford, J.C., Dannlowski, U., de Geus, E.J.C., Deary, I.J., Delanty, N., Depondt, C., Desrivières, S., Donohoe, G., Espeseth, T., Fernández, G., Fisher, S.E., Flor, H., Forstner, A.J., Francks, C., Franke, B., Glahn, D.C., Gollub, R.L., Grabe, H.J., Gruber, O., Håberg, A.K., Hariri, A.R., Hartman, C.A., Hashimoto, R., Heinz, A., Henskens, F.A., Hillegers, M.H.J., Hoekstra, P.J., Holmes, A.J., Hong, L.E., Hopkins, W.D., Hulshoff Pol, H.E., Jernigan, T.L., Jönsson, E.G., Kahn, R.S., Kennedy, M.A., Kircher, T.T.J., Kochunov, P., Kwok, J.B.J., Le Hellard, S., Loughland, C.M., Martin, N.G., Martinot, J-L, McDonald, C., McMahon, K.L., Meyer-Lindenberg, A., Michie, P.T., Morey, R.A., Mowry, B., Nyberg, L., Oosterlaan, J., Ophoff, R.A., Pantelis, C., Paus, T., Pausova, Z., Penninx, B.W.J.H., Polderman, T.J.C., Posthuma, D., Rietschel, M., Roffman, J.L., Rowland, L.M., Sachdev, P.S., Sämann, P.G., Schall, U., Schumann, G., Scott, R.J., Sim, K., Sisodiya, S.M., Smoller, J.W., Sommer, I.E., St Pourcain, B., Stein, D.J., Toga, A.W., Trollor, J.N., van der Wee, N.J.A., van ’t Ent, D., Völzke, H., Walter, H., Weber, B., Weinberger, D.R., Wright, M.J., Zhou, J., Stein, J.L., Thompson, P.M., and Medland, S.E.
Abstract: INTRODUCTION The cerebral cortex underlies our complex cognitive capabilities. Variations in human cortical surface area and thickness are associated with neurological, psychological, and behavioral traits and can be measured in vivo by magnetic resonance imaging (MRI). Studies in model organisms have identified genes that influence cortical structure, but little is known about common genetic variants that affect human cortical structure. RATIONALE To identify genetic variants associated with human cortical structure at both global and regional levels, we conducted a genome-wide association meta-analysis of brain MRI data from 51,665 individuals across 60 cohorts. We analyzed the surface area and average thickness of the whole cortex and 34 cortical regions with known functional specializations. RESULTS We identified 306 nominally genome-wide significant loci (P < 5 × 10−8) associated with cortical structure in a discovery sample of 33,992 participants of European ancestry. Of the 299 loci for which replication data were available, 241 loci influencing surface area and 14 influencing thickness remained significant after replication, with 199 loci passing multiple testing correction (P < 8.3 × 10−10; 187 influencing surface area and 12 influencing thickness). Common genetic variants explained 34% (SE = 3%) of the variation in total surface area and 26% (SE = 2%) in average thickness; surface area and thickness showed a negative genetic correlation (rG = −0.32, SE = 0.05, P = 6.5 × 10−12), which suggests that genetic influences have opposing effects on surface area and thickness. Bioinformatic analyses showed that total surface area is influenced by genetic variants that alter gene regulatory activity in neural progenitor cells during fetal development. By contrast, average thickness is influenced by active regulatory elements in adult brain samples, which may reflect processes that occur after mid-fetal development, such as myelination, branching, or pruning. When co
Published: 2020

7. The genetic architecture of the human cerebral cortex

Author: Grasby, KL, Jahanshad, N, Painter, JN, Colodro-Conde, L, Bralten, J, Hibar, DP, Lind, PA, Pizzagalli, F, Ching, CRK, McMahon, MAB, Shatokhina, N, Zsembik, LCP, Thomopoulos, SI, Zhu, AH, Strike, LT, Agartz, I, Alhusaini, S, Almeida, MAA, Alnaes, D, Amlien, IK, Andersson, M, Ard, T, Armstrong, NJ, Ashley-Koch, A, Atkins, JR, Bernard, M, Brouwer, RM, Buimer, EEL, Bulow, R, Burger, C, Cannon, DM, Chakravarty, M, Chen, Q, Cheung, JW, Couvy-Duchesne, B, Dale, AM, Dalvie, S, de Araujo, TK, de Zubicaray, GI, de Zwarte, SMC, den Braber, A, Nhat, TD, Dohm, K, Ehrlich, S, Engelbrecht, H-R, Erk, S, Fan, CC, Fedko, IO, Foley, SF, Ford, JM, Fukunaga, M, Garrett, ME, Ge, T, Giddaluru, S, Goldman, AL, Green, MJ, Groenewold, NA, Grotegerd, D, Gurholt, TP, Gutman, BA, Hansell, NK, Harris, MA, Harrison, MB, Haswell, CC, Hauser, M, Herms, S, Heslenfeld, DJ, Ho, NF, Hoehn, D, Hoffmann, P, Holleran, L, Hoogman, M, Hottenga, J-J, Ikeda, M, Janowitz, D, Jansen, IE, Jia, T, Jockwitz, C, Kanai, R, Karama, S, Kasperaviciute, D, Kaufmann, T, Kelly, S, Kikuchi, M, Klein, M, Knapp, M, Knodt, AR, Kramer, B, Lam, M, Lancaster, TM, Lee, PH, Lett, TA, Lewis, LB, Lopes-Cendes, I, Luciano, M, Macciardi, F, Marquand, AF, Mathias, SR, Melzer, TR, Milaneschi, Y, Mirza-Schreiber, N, Moreira, JCV, Muhleisen, TW, Mueller-Myhsok, B, Najt, P, Nakahara, S, Nho, K, Loohuis, LMO, Orfanos, DP, Pearson, JF, Pitcher, TL, Putz, B, Quide, Y, Ragothaman, A, Rashid, FM, Reay, WR, Redlich, R, Reinbold, CS, Repple, J, Richard, G, Riedel, BC, Risacher, SL, Rocha, CS, Mota, NR, Salminen, L, Saremi, A, Saykin, AJ, Schlag, F, Schmaal, L, Schofield, PR, Secolin, R, Shapland, CY, Shen, L, Shin, J, Shumskaya, E, Sonderby, IE, Sprooten, E, Tansey, KE, Teumer, A, Thalamuthu, A, Tordesillas-Gutierrez, D, Turner, JA, Uhlmann, A, Vallerga, CL, van der Meer, D, van Donkelaar, MMJ, van Eijk, L, van Erp, TGM, van Haren, NEM, van Rooij, D, van Tol, M-J, Veldink, JH, Verhoef, E, Walton, E, Wang, M, Wang, Y, Wardlaw, JM, Wen, W, Westlye, LT, Whelan, CD, Witt, SH, Wittfeld, K, Wolf, C, Wolfers, T, Wu, JQ, Yasuda, CL, Zaremba, D, Zhang, Z, Zwiers, MP, Artiges, E, Assareh, AA, Ayesa-Arriola, R, Belger, A, Brandt, CL, Brown, GG, Cichon, S, Curran, JE, Davies, GE, Degenhardt, F, Dennis, MF, Dietsche, B, Djurovic, S, Doherty, CP, Espiritu, R, Garijo, D, Gil, Y, Gowland, PA, Green, RC, Hausler, AN, Heindel, W, Ho, B-C, Hoffmann, WU, Holsboer, F, Homuth, G, Hosten, N, Jack, CR, Jang, M, Jansen, A, Kimbrel, NA, Kolskar, K, Koops, S, Krug, A, Lim, KO, Luykx, JJ, Mathalon, DH, Mather, KA, Mattay, VS, Matthews, S, Van Son, JM, McEwen, SC, Melle, I, Morris, DW, Mueller, BA, Nauck, M, Nordvik, JE, Noethen, MM, O'Leary, DS, Opel, N, Martinot, M-LP, Pike, GB, Preda, A, Quinlan, EB, Rasser, PE, Ratnakar, V, Reppermund, S, Steen, VM, Tooney, PA, Torres, FR, Veltman, DJ, Voyvodic, JT, Whelan, R, White, T, Yamamori, H, Adams, HHH, Bis, JC, Debette, S, Decarli, C, Fornage, M, Gudnason, V, Hofer, E, Ikram, MA, Launer, L, Longstreth, WT, Lopez, OL, Mazoyer, B, Mosley, TH, Roshchupkin, GV, Satizabal, CL, Schmidt, R, Seshadri, S, Yang, Q, Alvim, MKM, Ames, D, Anderson, TJ, Andreassen, OA, Arias-Vasquez, A, Bastin, ME, Baune, BT, Beckham, JC, Blangero, J, Boomsma, DI, Brodaty, H, Brunner, HG, Buckner, RL, Buitelaar, JK, Bustillo, JR, Cahn, W, Cairns, MJ, Calhoun, V, Carr, VJ, Caseras, X, Caspers, S, Cavalleri, GL, Cendes, F, Corvin, A, Crespo-Facorro, B, Dalrymple-Alford, JC, Dannlowski, U, de Geus, EJC, Deary, IJ, Delanty, N, Depondt, C, Desrivieres, S, Donohoe, G, Espeseth, T, Fernandez, G, Fisher, SE, Flor, H, Forstner, AJ, Francks, C, Franke, B, Glahn, DC, Gollub, RL, Grabe, HJ, Gruber, O, Haberg, AK, Hariri, AR, Hartman, CA, Hashimoto, R, Heinz, A, Henskens, FA, Hillegers, MHJ, Hoekstra, PJ, Holmes, AJ, Hong, LE, Hopkins, WD, Pol, HEH, Jernigan, TL, Jonsson, EG, Kahn, RS, Kennedy, MA, Kircher, TTJ, Kochunov, P, Kwok, JBJ, Le Hellard, S, Loughland, CM, Martin, NG, Martinot, J-L, McDonald, C, McMahon, KL, Meyer-Lindenberg, A, Michie, PT, Morey, RA, Mowry, B, Nyberg, L, Oosterlaan, J, Ophoff, RA, Pantelis, C, Paus, T, Pausova, Z, Penninx, BWJH, Polderman, TJC, Posthuma, D, Rietschel, M, Roffman, JL, Rowland, LM, Sachdev, PS, Samann, PG, Schall, U, Schumann, G, Scott, RJ, Sim, K, Sisodiya, SM, Smoller, JW, Sommer, IE, St Pourcain, B, Stein, DJ, Toga, AW, Trollor, JN, Van der Wee, NJA, van't Ent, D, Volzke, H, Walter, H, Weber, B, Weinberger, DR, Wright, MJ, Zhou, J, Stein, JL, Thompson, PM, Medland, SE, Grasby, KL, Jahanshad, N, Painter, JN, Colodro-Conde, L, Bralten, J, Hibar, DP, Lind, PA, Pizzagalli, F, Ching, CRK, McMahon, MAB, Shatokhina, N, Zsembik, LCP, Thomopoulos, SI, Zhu, AH, Strike, LT, Agartz, I, Alhusaini, S, Almeida, MAA, Alnaes, D, Amlien, IK, Andersson, M, Ard, T, Armstrong, NJ, Ashley-Koch, A, Atkins, JR, Bernard, M, Brouwer, RM, Buimer, EEL, Bulow, R, Burger, C, Cannon, DM, Chakravarty, M, Chen, Q, Cheung, JW, Couvy-Duchesne, B, Dale, AM, Dalvie, S, de Araujo, TK, de Zubicaray, GI, de Zwarte, SMC, den Braber, A, Nhat, TD, Dohm, K, Ehrlich, S, Engelbrecht, H-R, Erk, S, Fan, CC, Fedko, IO, Foley, SF, Ford, JM, Fukunaga, M, Garrett, ME, Ge, T, Giddaluru, S, Goldman, AL, Green, MJ, Groenewold, NA, Grotegerd, D, Gurholt, TP, Gutman, BA, Hansell, NK, Harris, MA, Harrison, MB, Haswell, CC, Hauser, M, Herms, S, Heslenfeld, DJ, Ho, NF, Hoehn, D, Hoffmann, P, Holleran, L, Hoogman, M, Hottenga, J-J, Ikeda, M, Janowitz, D, Jansen, IE, Jia, T, Jockwitz, C, Kanai, R, Karama, S, Kasperaviciute, D, Kaufmann, T, Kelly, S, Kikuchi, M, Klein, M, Knapp, M, Knodt, AR, Kramer, B, Lam, M, Lancaster, TM, Lee, PH, Lett, TA, Lewis, LB, Lopes-Cendes, I, Luciano, M, Macciardi, F, Marquand, AF, Mathias, SR, Melzer, TR, Milaneschi, Y, Mirza-Schreiber, N, Moreira, JCV, Muhleisen, TW, Mueller-Myhsok, B, Najt, P, Nakahara, S, Nho, K, Loohuis, LMO, Orfanos, DP, Pearson, JF, Pitcher, TL, Putz, B, Quide, Y, Ragothaman, A, Rashid, FM, Reay, WR, Redlich, R, Reinbold, CS, Repple, J, Richard, G, Riedel, BC, Risacher, SL, Rocha, CS, Mota, NR, Salminen, L, Saremi, A, Saykin, AJ, Schlag, F, Schmaal, L, Schofield, PR, Secolin, R, Shapland, CY, Shen, L, Shin, J, Shumskaya, E, Sonderby, IE, Sprooten, E, Tansey, KE, Teumer, A, Thalamuthu, A, Tordesillas-Gutierrez, D, Turner, JA, Uhlmann, A, Vallerga, CL, van der Meer, D, van Donkelaar, MMJ, van Eijk, L, van Erp, TGM, van Haren, NEM, van Rooij, D, van Tol, M-J, Veldink, JH, Verhoef, E, Walton, E, Wang, M, Wang, Y, Wardlaw, JM, Wen, W, Westlye, LT, Whelan, CD, Witt, SH, Wittfeld, K, Wolf, C, Wolfers, T, Wu, JQ, Yasuda, CL, Zaremba, D, Zhang, Z, Zwiers, MP, Artiges, E, Assareh, AA, Ayesa-Arriola, R, Belger, A, Brandt, CL, Brown, GG, Cichon, S, Curran, JE, Davies, GE, Degenhardt, F, Dennis, MF, Dietsche, B, Djurovic, S, Doherty, CP, Espiritu, R, Garijo, D, Gil, Y, Gowland, PA, Green, RC, Hausler, AN, Heindel, W, Ho, B-C, Hoffmann, WU, Holsboer, F, Homuth, G, Hosten, N, Jack, CR, Jang, M, Jansen, A, Kimbrel, NA, Kolskar, K, Koops, S, Krug, A, Lim, KO, Luykx, JJ, Mathalon, DH, Mather, KA, Mattay, VS, Matthews, S, Van Son, JM, McEwen, SC, Melle, I, Morris, DW, Mueller, BA, Nauck, M, Nordvik, JE, Noethen, MM, O'Leary, DS, Opel, N, Martinot, M-LP, Pike, GB, Preda, A, Quinlan, EB, Rasser, PE, Ratnakar, V, Reppermund, S, Steen, VM, Tooney, PA, Torres, FR, Veltman, DJ, Voyvodic, JT, Whelan, R, White, T, Yamamori, H, Adams, HHH, Bis, JC, Debette, S, Decarli, C, Fornage, M, Gudnason, V, Hofer, E, Ikram, MA, Launer, L, Longstreth, WT, Lopez, OL, Mazoyer, B, Mosley, TH, Roshchupkin, GV, Satizabal, CL, Schmidt, R, Seshadri, S, Yang, Q, Alvim, MKM, Ames, D, Anderson, TJ, Andreassen, OA, Arias-Vasquez, A, Bastin, ME, Baune, BT, Beckham, JC, Blangero, J, Boomsma, DI, Brodaty, H, Brunner, HG, Buckner, RL, Buitelaar, JK, Bustillo, JR, Cahn, W, Cairns, MJ, Calhoun, V, Carr, VJ, Caseras, X, Caspers, S, Cavalleri, GL, Cendes, F, Corvin, A, Crespo-Facorro, B, Dalrymple-Alford, JC, Dannlowski, U, de Geus, EJC, Deary, IJ, Delanty, N, Depondt, C, Desrivieres, S, Donohoe, G, Espeseth, T, Fernandez, G, Fisher, SE, Flor, H, Forstner, AJ, Francks, C, Franke, B, Glahn, DC, Gollub, RL, Grabe, HJ, Gruber, O, Haberg, AK, Hariri, AR, Hartman, CA, Hashimoto, R, Heinz, A, Henskens, FA, Hillegers, MHJ, Hoekstra, PJ, Holmes, AJ, Hong, LE, Hopkins, WD, Pol, HEH, Jernigan, TL, Jonsson, EG, Kahn, RS, Kennedy, MA, Kircher, TTJ, Kochunov, P, Kwok, JBJ, Le Hellard, S, Loughland, CM, Martin, NG, Martinot, J-L, McDonald, C, McMahon, KL, Meyer-Lindenberg, A, Michie, PT, Morey, RA, Mowry, B, Nyberg, L, Oosterlaan, J, Ophoff, RA, Pantelis, C, Paus, T, Pausova, Z, Penninx, BWJH, Polderman, TJC, Posthuma, D, Rietschel, M, Roffman, JL, Rowland, LM, Sachdev, PS, Samann, PG, Schall, U, Schumann, G, Scott, RJ, Sim, K, Sisodiya, SM, Smoller, JW, Sommer, IE, St Pourcain, B, Stein, DJ, Toga, AW, Trollor, JN, Van der Wee, NJA, van't Ent, D, Volzke, H, Walter, H, Weber, B, Weinberger, DR, Wright, MJ, Zhou, J, Stein, JL, Thompson, PM, and Medland, SE
Abstract: The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.
Published: 2020

8. Genetic architecture of subcortical brain structures in 38,851 individuals

Author: SATIZABAL, C. L., ADAMS, H. H. H., HIBAR, D. P., WHITE, C. C., KNOL, M. J., STEIN, J. L., Scholz, M., Sargurupremraj, Muralidharan, JAHANSHAD, N., ROSHCHUPKIN, G. V., SMITH, A. V., BIS, J. C., JIAN, X., LUCIANO, M., Hofer, E., TEUMER, A., VAN DER LEE, S. J., Yang, J., YANEK, L. R., LEE, T. V., Li, S., Hu, Y., KOH, J. Y., EICHER, J. D., DESRIVIERES, S., ARIAS-VASQUEZ, A., Chauhan, G., ATHANASIU, L., RENTERIA, M. E., Kim, S., HOEHN, D., ARMSTRONG, N. J., Chen, Q., HOLMES, A. J., DEN BRABER, A., KLOSZEWSKA, I., Andersson, M., ESPESETH, T., Grimm, O., ABRAMOVIC, L., ALHUSAINI, S., MILANESCHI, Y., PAPMEYER, M., AXELSSON, T., Ehrlich, S., ROIZ-SANTIANEZ, R., KRAEMER, B., HABERG, A. K., JONES, H. J., Pike, G. B., STEIN, D. J., Stevens, A., BRALTEN, J., VERNOOIJ, M. W., HARRIS, T. B., FILIPPI, I., WITTE, A. V., Guadalupe, T., WITTFELD, K., MOSLEY, T. H., BECKER, J. T., DOAN, N. T., HAGENAARS, S. P., SABA, Y., CUELLAR-PARTIDA, G., Amin, N., HILAL, S., NHO, K., MIRZA-SCHREIBER, N., ARFANAKIS, K., BECKER, D. M., Ames, D., GOLDMAN, A. L., LEE, P. H., Boomsma, D. I., LOVESTONE, S., GIDDALURU, S., LE HELLARD, S., Mattheisen, M., BOHLKEN, M. M., KASPERAVICIUTE, D., SCHMAAL, L., LAWRIE, S. M., Agartz, I., Walton, E., TORDESILLAS-GUTIERREZ, D., DAVIES, G. E., Shin, J., IPSER, J. C., VINKE, L. N., HOOGMAN, M., Jia, T., BURKHARDT, R., Klein, M., Crivello, Fabrice, JANOWITZ, D., CARMICHAEL, O., HAUKVIK, U. K., ARIBISALA, B. S., Schmidt, H., STRIKE, L. T., CHENG, C. Y., RISACHER, S. L., PUTZ, B., FLEISCHMAN, D. A., ASSAREH, A. A., MATTAY, V. S., BUCKNER, R. L., MECOCCI, P., DALE, A. M., Cichon, S., BOKS, M. P., MATARIN, M., PENNINX, Bwjh, CALHOUN, V. D., CHAKRAVARTY, M. M., MARQUAND, A. F., MACARE, C., KHARABIAN MASOULEH, S., OOSTERLAAN, J., Amouyel, P., HEGENSCHEID, K., ROTTER, J. I., SCHORK, A. J., LIEWALD, D. C. M., DE ZUBICARAY, G. I., WONG, T. Y., Shen, L., SAMANN, P. G., BRODATY, H., ROFFMAN, J. L., DE GEUS, E. J. C., TSOLAKI, M., ERK, S., VAN EIJK, K. R., CAVALLERI, G. L., VAN DER WEE, N. J. A., MCINTOSH, A. M., GOLLUB, R. L., BULAYEVA, K. B., Bernard, M., RICHARDS, J. S., HIMALI, J. J., Loeffler, M., ROMMELSE, N., Hoffmann, W., WESTLYE, L. T., VALDES HERNANDEZ, M. C., HANSELL, N. K., VAN ERP, T. G. M., Wolf, C., KWOK, J. B. J., Vellas, B., Heinz, A., OLDE LOOHUIS, L. M., DELANTY, N., HO, B. C., CHING, C. R. K., SHUMSKAYA, E., Singh, B., Hofman, A., VAN DER MEER, D., Homuth, G., PSATY, B. M., BASTIN, M. E., MONTGOMERY, G. W., FOROUD, T. M., REPPERMUND, S., HOTTENGA, J. J., Simmons, A., Meyer-Lindenberg, A., Cahn, W., WHELAN, C. D., VAN DONKELAAR, M. M. J., Yang, Q., HOSTEN, N., GREEN, R. C., THALAMUTHU, A., MOHNKE, S., HULSHOFF POL, H. E., Lin, H., JACK, C. R., Jr., SCHOFIELD, P. R., MUHLEISEN, T. W., MAILLARD, P., POTKIN, S. G., Wen, W., FLETCHER, E., TOGA, A. W., Gruber, O., HUENTELMAN, M., DAVEY SMITH, G., LAUNER, L. J., Nyberg, L., JONSSON, E. G., CRESPO-FACORRO, B., KOEN, N., GREVE, D. N., UITTERLINDEN, A. G., WEINBERGER, D. R., STEEN, V. M., FEDKO, I. O., GROENEWOLD, N. A., Niessen, W. J., TORO, R., Tzourio, Christophe, LONGSTRETH, W. T., Jr., SMOLLER, J. W., VAN TOL, M. J., SUSSMANN, J. E., PAUS, T., Lemaitre, H., SCHROETER, M. L., Mazoyer, B., ANDREASSEN, O. A., Holsboer, F., DEPONDT, C., VELTMAN, D. J., Turner, J. A., PAUSOVA, Z., Schumann, G., Van Rooij, D., Djurovic, S., DEARY, I. J., MCMAHON, K. L., MULLER-MYHSOK, B., BROUWER, R. M., Soininen, H., Pandolfo, M., WASSINK, T. H., CHEUNG, J. W., WOLFERS, T., MARTINOT, J. L., ZWIERS, M. P., Nauck, M., Melle, I., Martin, N. G., Kanai, R., WESTMAN, E., KAHN, R. S., Sisodiya, S. M., White, T., SAREMI, A., van Bokhoven, H., Brunner, H. G., VOLZKE, H., WRIGHT, M. J., VAN 'T ENT, D., NOTHEN, M. M., OPHOFF, R. A., BUITELAAR, J. K., Fernandez, G., SACHDEV, P. S., Rietschel, M., VAN HAREN, N. E. M., Fisher, S. E., BEISER, A. S., Francks, C., SAYKIN, A. J., MATHER, K. A., ROMANCZUK-SEIFERTH, N., HARTMAN, C. A., DeStefano, A. L., HESLENFELD, D. J., WEINER, M. W., Walter, H., HOEKSTRA, P. J., NYQUIST, P. A., Franke, B., BENNETT, D. A., Grabe, H. J., JOHNSON, A. D., Chen, C., VAN DUIJN, C. M., LOPEZ, O. L., FORNAGE, M., WARDLAW, J. M., Schmidt, R., DeCarli, C., DE JAGER, P. L., VILLRINGER, A., Debette, Stephanie, GUDNASON, V., Medland, S. E., SHULMAN, J. M., THOMPSON, P. M., SESHADRI, S., IKRAM, M. K., Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Neurosciences cognitives et intégratives d'Aquitaine (INCIA), and Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1-SFR Bordeaux Neurosciences-Centre National de la Recherche Scientifique (CNRS)
Subjects: nervous system, VINTAGE, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, HEALTHY
Abstract: Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.
Published: 2019

9. Genetic architecture of subcortical brain structures in 38,851 individuals

Author: Satizabal, C.L., Adams, H.H.H., Hibar, D.P., White, C.C., Knol, M.J., Stein, J.L., Scholz, M., Sargurupremraj, M., Jahanshad, N., Roshchupkin, G.V., Smith, A.V., Bis, J.C., Jian, X., Luciano, M., Hofer, E., Teumer, A., van der Lee, S.J., Yang, J., Yanek, L.R., Lee, T.V., Li, S., Hu, Y., Koh, J.Y., Eicher, J.D., Desrivières, S., Arias-Vasquez, A., Chauhan, G., Athanasiu, L., Renteria, M.E., Kim, S., Hoehn, D., Armstrong, N.J., Chen, Q., Holmes, A.J., den Braber, A., Kloszewska, I., Andersson, M., Espeseth, T., Grimm, O., Abramovic, L., Alhusaini, S., Milaneschi, Y., Papmeyer, M., Axelsson, T., Ehrlich, S., Roiz-Santiañez, R., Kraemer, B., Håberg, A.K., Jones, H.J., Pike, G.B., Stein, D.J., Stevens, A., Bralten, J., Vernooij, M.W., Harris, T.B., Filippi, I., Witte, A.V., Guadalupe, T., Wittfeld, K., Mosley, T.H., Becker, J.T., Doan, N.T., Hagenaars, S.P., Saba, Y., Cuellar-Partida, G., Amin, N., Hilal, S., Nho, K., Mirza-Schreiber, N., Arfanakis, K., Becker, D.M., Ames, D., Goldman, A.L., Lee, P.H., Boomsma, D.I., Lovestone, S., Giddaluru, S., Le Hellard, S., Mattheisen, M., Bohlken, M.M., Kasperaviciute, D., Schmaal, L., Lawrie, S.M., Agartz, I., Walton, E., Tordesillas-Gutierrez, D., Davies, G.E., Shin, J., Ipser, J.C., Vinke, L.N., Hoogman, M., Jia, T., Burkhardt, R., Klein, M., Crivello, F., Janowitz, D., Carmichael, O., Haukvik, U.K., Aribisala, B.S., Schmidt, H., Strike, L.T., Cheng, C-Y, Risacher, S.L., Pütz, B., Fleischman, D.A., Assareh, A.A., Mattay, V.S., Buckner, R.L., Mecocci, P., Dale, A.M., Cichon, S., Boks, M.P., Matarin, M., Penninx, B.W.J.H., Calhoun, V.D., Chakravarty, M.M., Marquand, A.F., Macare, C., Kharabian Masouleh, S., Oosterlaan, J., Amouyel, P., Hegenscheid, K., Rotter, J.I., Schork, A.J., Liewald, D.C.M., de Zubicaray, G.I., Wong, T.Y., Shen, L., Sämann, P.G., Brodaty, H., Roffman, J.L., de Geus, E.J.C., Tsolaki, M., Erk, S., van Eijk, K.R., Cavalleri, G.L., van der Wee, N.J.A., McIntosh, A.M., Gollub, R.L., Bulayeva, K.B., Bernard, M., Richards, J.S., Himali, J.J., Loeffler, M., Rommelse, N., Hoffmann, W., Westlye, L.T., Valdés Hernández, M.C., Hansell, N.K., Van Erp, T.G.M., Wolf, C., Kwok, J.B.J., Vellas, B., Heinz, A., Olde Loohuis, L.M., Delanty, N., Ho, B-C., Ching, C.R.K., Shumskaya, E., Singh, B., Hofman, A., van der Meer, D., Homuth, G., Psaty, B.M., Bastin, M.E., Montgomery, G.W., Foroud, T.M., Reppermund, S., Hottenga, J-J, Simmons, A., Meyer-Lindenberg, A., Cahn, W., Whelan, C.D., van Donkelaar, M.M.J., Yang, Q., Hosten, N., Green, R.C., Thalamuthu, A., Mohnke, S., Hulshoff Pol, H.E., Lin, H., Jack, C.R., Schofield, P.R., Mühleisen, T.W., Maillard, P., Potkin, S.G., Wen, W., Fletcher, E., Toga, A.W., Gruber, O., Huentelman, M., Davey Smith, G., Launer, L.J., Nyberg, L., Jönsson, E.G., Crespo-Facorro, B., Koen, N., Greve, D.N., Uitterlinden, A.G., Weinberger, D.R., Steen, V.M., Fedko, I.O., Groenewold, N.A., Niessen, W.J., Toro, R., Tzourio, C., Longstreth, W.T., Ikram, M.K., Smoller, J.W., van Tol, M-J, Sussmann, J.E., Paus, T., Lemaitre, H., Schroeter, M.L., Mazoyer, B., Andreassen, O.A., Holsboer, F., Depondt, C., Veltman, D.J., Turner, J.A., Pausova, Z., Schumann, G., Van Rooij, D., Djurovic, S., Deary, I.J., McMahon, K.L., Müller-Myhsok, B., Brouwer, R.M., Soininen, H., Pandolfo, M., Wassink, T.H., Cheung, J.W., Wolfers, T., Martinot, J-L, Zwiers, M.P., Nauck, M., Melle, I., Martin, N.G., Kanai, R., Westman, E., Kahn, R.S., Sisodiya, S.M., White, T., Saremi, A., van Bokhoven, H., Brunner, H.G., Völzke, H., Wright, M.J., van ‘t Ent, D., Nöthen, M.M., Ophoff, R.A., Buitelaar, J.K., Fernández, G., Sachdev, P.S., Rietschel, M., van Haren, N.E.M., Fisher, S.E., Beiser, A.S., Francks, C., Saykin, A.J., Mather, K.A., Romanczuk-Seiferth, N., Hartman, C.A., DeStefano, A.L., Heslenfeld, D.J., Weiner, M.W., Walter, H., Hoekstra, P.J., Nyquist, P.A., Franke, B., Bennett, D.A., Grabe, H.J., Johnson, A.D., Chen, C., van Duijn, C.M., Lopez, O.L., Fornage, M., Wardlaw, J.M., Schmidt, R., DeCarli, C., De Jager, P.L., Villringer, A., Debette, S., Gudnason, V., Medland, S.E., Shulman, J.M., Thompson, P.M., Seshadri, S., Ikram, M.A., Satizabal, C.L., Adams, H.H.H., Hibar, D.P., White, C.C., Knol, M.J., Stein, J.L., Scholz, M., Sargurupremraj, M., Jahanshad, N., Roshchupkin, G.V., Smith, A.V., Bis, J.C., Jian, X., Luciano, M., Hofer, E., Teumer, A., van der Lee, S.J., Yang, J., Yanek, L.R., Lee, T.V., Li, S., Hu, Y., Koh, J.Y., Eicher, J.D., Desrivières, S., Arias-Vasquez, A., Chauhan, G., Athanasiu, L., Renteria, M.E., Kim, S., Hoehn, D., Armstrong, N.J., Chen, Q., Holmes, A.J., den Braber, A., Kloszewska, I., Andersson, M., Espeseth, T., Grimm, O., Abramovic, L., Alhusaini, S., Milaneschi, Y., Papmeyer, M., Axelsson, T., Ehrlich, S., Roiz-Santiañez, R., Kraemer, B., Håberg, A.K., Jones, H.J., Pike, G.B., Stein, D.J., Stevens, A., Bralten, J., Vernooij, M.W., Harris, T.B., Filippi, I., Witte, A.V., Guadalupe, T., Wittfeld, K., Mosley, T.H., Becker, J.T., Doan, N.T., Hagenaars, S.P., Saba, Y., Cuellar-Partida, G., Amin, N., Hilal, S., Nho, K., Mirza-Schreiber, N., Arfanakis, K., Becker, D.M., Ames, D., Goldman, A.L., Lee, P.H., Boomsma, D.I., Lovestone, S., Giddaluru, S., Le Hellard, S., Mattheisen, M., Bohlken, M.M., Kasperaviciute, D., Schmaal, L., Lawrie, S.M., Agartz, I., Walton, E., Tordesillas-Gutierrez, D., Davies, G.E., Shin, J., Ipser, J.C., Vinke, L.N., Hoogman, M., Jia, T., Burkhardt, R., Klein, M., Crivello, F., Janowitz, D., Carmichael, O., Haukvik, U.K., Aribisala, B.S., Schmidt, H., Strike, L.T., Cheng, C-Y, Risacher, S.L., Pütz, B., Fleischman, D.A., Assareh, A.A., Mattay, V.S., Buckner, R.L., Mecocci, P., Dale, A.M., Cichon, S., Boks, M.P., Matarin, M., Penninx, B.W.J.H., Calhoun, V.D., Chakravarty, M.M., Marquand, A.F., Macare, C., Kharabian Masouleh, S., Oosterlaan, J., Amouyel, P., Hegenscheid, K., Rotter, J.I., Schork, A.J., Liewald, D.C.M., de Zubicaray, G.I., Wong, T.Y., Shen, L., Sämann, P.G., Brodaty, H., Roffman, J.L., de Geus, E.J.C., Tsolaki, M., Erk, S., van Eijk, K.R., Cavalleri, G.L., van der Wee, N.J.A., McIntosh, A.M., Gollub, R.L., Bulayeva, K.B., Bernard, M., Richards, J.S., Himali, J.J., Loeffler, M., Rommelse, N., Hoffmann, W., Westlye, L.T., Valdés Hernández, M.C., Hansell, N.K., Van Erp, T.G.M., Wolf, C., Kwok, J.B.J., Vellas, B., Heinz, A., Olde Loohuis, L.M., Delanty, N., Ho, B-C., Ching, C.R.K., Shumskaya, E., Singh, B., Hofman, A., van der Meer, D., Homuth, G., Psaty, B.M., Bastin, M.E., Montgomery, G.W., Foroud, T.M., Reppermund, S., Hottenga, J-J, Simmons, A., Meyer-Lindenberg, A., Cahn, W., Whelan, C.D., van Donkelaar, M.M.J., Yang, Q., Hosten, N., Green, R.C., Thalamuthu, A., Mohnke, S., Hulshoff Pol, H.E., Lin, H., Jack, C.R., Schofield, P.R., Mühleisen, T.W., Maillard, P., Potkin, S.G., Wen, W., Fletcher, E., Toga, A.W., Gruber, O., Huentelman, M., Davey Smith, G., Launer, L.J., Nyberg, L., Jönsson, E.G., Crespo-Facorro, B., Koen, N., Greve, D.N., Uitterlinden, A.G., Weinberger, D.R., Steen, V.M., Fedko, I.O., Groenewold, N.A., Niessen, W.J., Toro, R., Tzourio, C., Longstreth, W.T., Ikram, M.K., Smoller, J.W., van Tol, M-J, Sussmann, J.E., Paus, T., Lemaitre, H., Schroeter, M.L., Mazoyer, B., Andreassen, O.A., Holsboer, F., Depondt, C., Veltman, D.J., Turner, J.A., Pausova, Z., Schumann, G., Van Rooij, D., Djurovic, S., Deary, I.J., McMahon, K.L., Müller-Myhsok, B., Brouwer, R.M., Soininen, H., Pandolfo, M., Wassink, T.H., Cheung, J.W., Wolfers, T., Martinot, J-L, Zwiers, M.P., Nauck, M., Melle, I., Martin, N.G., Kanai, R., Westman, E., Kahn, R.S., Sisodiya, S.M., White, T., Saremi, A., van Bokhoven, H., Brunner, H.G., Völzke, H., Wright, M.J., van ‘t Ent, D., Nöthen, M.M., Ophoff, R.A., Buitelaar, J.K., Fernández, G., Sachdev, P.S., Rietschel, M., van Haren, N.E.M., Fisher, S.E., Beiser, A.S., Francks, C., Saykin, A.J., Mather, K.A., Romanczuk-Seiferth, N., Hartman, C.A., DeStefano, A.L., Heslenfeld, D.J., Weiner, M.W., Walter, H., Hoekstra, P.J., Nyquist, P.A., Franke, B., Bennett, D.A., Grabe, H.J., Johnson, A.D., Chen, C., van Duijn, C.M., Lopez, O.L., Fornage, M., Wardlaw, J.M., Schmidt, R., DeCarli, C., De Jager, P.L., Villringer, A., Debette, S., Gudnason, V., Medland, S.E., Shulman, J.M., Thompson, P.M., Seshadri, S., and Ikram, M.A.
Abstract: Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.
Published: 2019

10. Novel genetic loci underlying human intracranial volume identified through genome-wide association

Author: Adams, H.H.H., Hibar, D.P., Chouraki, V., Stein, J.L., Nyquist, P.A., Renteria, M.E., Trompet, S., Arias-Vasquez, A., Seshadri, S., Desrivières, S., Beecham, A.H., Jahanshad, N., Wittfeld, K., van der Lee, S.J., Abramovic, L., Alhusaini, S., Amin, N., Andersson, M., Arfanakis, K., Aribisala, B.S., Armstrong, N.J., Athanasiu, L., Axelsson, T., Beiser, A., Bernard, M., Bis, J.C., Blanken, L.M.E., Blanton, S.H., Bohlken, M.M., Boks, M.P., Bralten, J., Brickman, A.M., Carmichael, O., Chakravarty, M.M., Chauhan, G., Chen, Q., Ching, C.R.K., Cuellar-Partida, G., Braber, A.D., Doan, N.T., Ehrlich, S., Filippi, I., Ge, T., Giddaluru, S., Goldman, A.L., Gottesman, R.F., Greven, C.U., Grimm, O., Griswold, M.E., Guadalupe, T., Hass, J., Haukvik, U.K., Hilal, S., Hofer, E., Hoehn, D., Holmes, A.J., Hoogman, M., Janowitz, D., Jia, T., Kasperaviciute, D., Kim, S., Klein, M., Kraemer, B., Lee, P.H., Liao, J., Liewald, D.C.M., Lopez, L.M., Luciano, M., Macare, C., Marquand, A., Matarin, M., Mather, K.A., Mattheisen, M., Mazoyer, B., McKay, D.R., McWhirter, R., Milaneschi, Y., Mirza-Schreiber, N., Muetzel, R.L., Maniega, S.M., Nho, K., Nugent, A.C., Loohuis, L.M.O., Oosterlaan, J., Papmeyer, M., Pappa, I., Pirpamer, L., Pudas, S., Pütz, B., Rajan, K.B., Ramasamy, A., Richards, J.S., Risacher, S.L., Roiz-Santiañez, R., Rommelse, N., Rose, E.J., Royle, N.A., Rundek, T., Sämann, P.G., Satizabal, C.L., Schmaal, L., Schork, A.J., Shen, L., Shin, J., Shumskaya, E., Smith, A.V., Sprooten, E., Strike, L.T., Teumer, A., Thomson, R., Tordesillas-Gutierrez, D., Toro, R., Trabzuni, D., Vaidya, D., Van der Grond, J., van der Meer, D., van Donkelaar, M.M.J., van Eijk, K.R., Van Erp, T.G.M., Van Rooij, D., Walton, E., Westlye, L.T., Whelan, C.D., Windham, B.G., Winkler, A.M., Woldehawariat, G., Wolf, C., Wolfers, T., Xu, B., Yanek, L.R., Yang, J., Zijdenbos, A., Zwiers, M.P., Agartz, I., Aggarwal, N.T., Almasy, L., Ames, D., Amouyel, P., Andreassen, O.A., Arepalli, S., Assareh, A.A., Barral, S., Bastin, M.E., Becker, D.M., Becker, J.T., Bennett, D.A., Blangero, J., van Bokhoven, H., Boomsma, D.I., Brodaty, H., Brouwer, R.M., Brunner, H.G., Buckner, R.L., Buitelaar, J.K., Bulayeva, K.B., Cahn, W., Calhoun, V.D., Cannon, D.M., Cavalleri, G.L., Chen, C., Cheng, C-Y, Cichon, S., Cookson, M.R., Corvin, A., Crespo-Facorro, B., Curran, J.E., Czisch, M., Dale, A.M., Davies, G.E., De Geus, E.J.C., De Jager, P.L., de Zubicaray, G.I., Delanty, N., Depondt, C., DeStefano, A.L., Dillman, A., Djurovic, S., Donohoe, G., Drevets, W.C., Duggirala, R., Dyer, T.D., Erk, S., Espeseth, T., Evans, D.A., Fedko, I.O., Fernández, G., Ferrucci, L., Fisher, S.E., Fleischman, D.A., Ford, I., Foroud, T.M., Fox, P.T., Francks, C., Fukunaga, M., Gibbs, J.R., Glahn, D.C., Gollub, R.L., Göring, H.H.H., Grabe, H.J., Green, R.C., Gruber, O., Gudnason, V., Guelfi, S., Hansell, N.K., Hardy, J., Hartman, C.A., Hashimoto, R., Hegenscheid, K., Heinz, A., Le Hellard, S., Hernandez, D.G., Heslenfeld, D.J., Ho, B-C., Hoekstra, P.J., Hoffmann, W., Hofman, A., Holsboer, F., Homuth, G., Hosten, N., Hottenga, J-J, Pol, H.E.H., Ikeda, M., Ikram, M.K., Jack, C.R., Jenkinson, M., Johnson, R., Jönsson, E.G., Jukema, J.W., Kahn, R.S., Kanai, R., Kloszewska, I., Knopman, D.S., Kochunov, P., Kwok, J.B., Lawrie, S.M., Lemaitre, H., Liu, X., Longo, D.L., Longstreth, W.T., Lopez, O.L., Lovestone, S., Martinez, O.P., Martinot, J-L, Mattay, V.S., McDonald, C., McIntosh, A.M., McMahon, K.L., McMahon, F.J., Mecocci, P., Melle, I., Meyer-Lindenberg, A., Mohnke, S., Montgomery, G.W., Morris, D.W., Mosley, T.H., Mühleisen, T.W., Müller-Myhsok, B., Nalls, M.A., Nauck, M., Nichols, T.E., Niessen, W.J., Nöthen, M.M., Nyberg, L., Ohi, K., Olvera, R.L., Ophoff, R.A., Pandolfo, M., Paus, T., Pausova, Z., Penninx, B.W.J.H., Pike, G.B., Potkin, S.G., Psaty, B.M., Reppermund, S., Rietschel, M., Roffman, J.L., Romanczuk-Seiferth, N., Rotter, J.I., Ryten, M., Sacco, R.L., Sachdev, P.S., Saykin, A.J., Schmidt, R., Schofield, P.R., Sigurdsson, S., Simmons, A., Singleton, A., Sisodiya, S.M., Smith, C., Smoller, J.W., Soininen, H., Srikanth, V., Steen, V.M., Stott, D.J., Sussmann, J.E., Thalamuthu, A., Tiemeier, H., Toga, A.W., Traynor, B.J., Troncoso, J., Turner, J.A., Tzourio, C., Uitterlinden, A.G., Hernández, M.C.V., van der Brug, M., Van der Lugt, A., van der Wee, N.J.A., van Duijn, C.M., van Haren, N.E.M., Van′t Ent, D., van Tol, M-J, Vardarajan, B.N., Veltman, D.J., Vernooij, M.W., Volzke, H., Walter, H., Wardlaw, J.M., Wassink, T.H., Weale, M.E., Weinberger, D.R., Weiner, M.W., Wen, W., Westman, E., White, T., Wong, T.Y., Wright, C.B., Zielke, H.R., Zonderman, A.B., Deary, I.J., DeCarli, C., Schmidt, H., Martin, N.G., de Craen, A.J.M., Wright, M.J., Launer, L.J., Schumann, G., Fornage, M., Franke, B., Debette, S., Medland, S.E., Ikram, M.A., Thompson, P.M., Adams, H.H.H., Hibar, D.P., Chouraki, V., Stein, J.L., Nyquist, P.A., Renteria, M.E., Trompet, S., Arias-Vasquez, A., Seshadri, S., Desrivières, S., Beecham, A.H., Jahanshad, N., Wittfeld, K., van der Lee, S.J., Abramovic, L., Alhusaini, S., Amin, N., Andersson, M., Arfanakis, K., Aribisala, B.S., Armstrong, N.J., Athanasiu, L., Axelsson, T., Beiser, A., Bernard, M., Bis, J.C., Blanken, L.M.E., Blanton, S.H., Bohlken, M.M., Boks, M.P., Bralten, J., Brickman, A.M., Carmichael, O., Chakravarty, M.M., Chauhan, G., Chen, Q., Ching, C.R.K., Cuellar-Partida, G., Braber, A.D., Doan, N.T., Ehrlich, S., Filippi, I., Ge, T., Giddaluru, S., Goldman, A.L., Gottesman, R.F., Greven, C.U., Grimm, O., Griswold, M.E., Guadalupe, T., Hass, J., Haukvik, U.K., Hilal, S., Hofer, E., Hoehn, D., Holmes, A.J., Hoogman, M., Janowitz, D., Jia, T., Kasperaviciute, D., Kim, S., Klein, M., Kraemer, B., Lee, P.H., Liao, J., Liewald, D.C.M., Lopez, L.M., Luciano, M., Macare, C., Marquand, A., Matarin, M., Mather, K.A., Mattheisen, M., Mazoyer, B., McKay, D.R., McWhirter, R., Milaneschi, Y., Mirza-Schreiber, N., Muetzel, R.L., Maniega, S.M., Nho, K., Nugent, A.C., Loohuis, L.M.O., Oosterlaan, J., Papmeyer, M., Pappa, I., Pirpamer, L., Pudas, S., Pütz, B., Rajan, K.B., Ramasamy, A., Richards, J.S., Risacher, S.L., Roiz-Santiañez, R., Rommelse, N., Rose, E.J., Royle, N.A., Rundek, T., Sämann, P.G., Satizabal, C.L., Schmaal, L., Schork, A.J., Shen, L., Shin, J., Shumskaya, E., Smith, A.V., Sprooten, E., Strike, L.T., Teumer, A., Thomson, R., Tordesillas-Gutierrez, D., Toro, R., Trabzuni, D., Vaidya, D., Van der Grond, J., van der Meer, D., van Donkelaar, M.M.J., van Eijk, K.R., Van Erp, T.G.M., Van Rooij, D., Walton, E., Westlye, L.T., Whelan, C.D., Windham, B.G., Winkler, A.M., Woldehawariat, G., Wolf, C., Wolfers, T., Xu, B., Yanek, L.R., Yang, J., Zijdenbos, A., Zwiers, M.P., Agartz, I., Aggarwal, N.T., Almasy, L., Ames, D., Amouyel, P., Andreassen, O.A., Arepalli, S., Assareh, A.A., Barral, S., Bastin, M.E., Becker, D.M., Becker, J.T., Bennett, D.A., Blangero, J., van Bokhoven, H., Boomsma, D.I., Brodaty, H., Brouwer, R.M., Brunner, H.G., Buckner, R.L., Buitelaar, J.K., Bulayeva, K.B., Cahn, W., Calhoun, V.D., Cannon, D.M., Cavalleri, G.L., Chen, C., Cheng, C-Y, Cichon, S., Cookson, M.R., Corvin, A., Crespo-Facorro, B., Curran, J.E., Czisch, M., Dale, A.M., Davies, G.E., De Geus, E.J.C., De Jager, P.L., de Zubicaray, G.I., Delanty, N., Depondt, C., DeStefano, A.L., Dillman, A., Djurovic, S., Donohoe, G., Drevets, W.C., Duggirala, R., Dyer, T.D., Erk, S., Espeseth, T., Evans, D.A., Fedko, I.O., Fernández, G., Ferrucci, L., Fisher, S.E., Fleischman, D.A., Ford, I., Foroud, T.M., Fox, P.T., Francks, C., Fukunaga, M., Gibbs, J.R., Glahn, D.C., Gollub, R.L., Göring, H.H.H., Grabe, H.J., Green, R.C., Gruber, O., Gudnason, V., Guelfi, S., Hansell, N.K., Hardy, J., Hartman, C.A., Hashimoto, R., Hegenscheid, K., Heinz, A., Le Hellard, S., Hernandez, D.G., Heslenfeld, D.J., Ho, B-C., Hoekstra, P.J., Hoffmann, W., Hofman, A., Holsboer, F., Homuth, G., Hosten, N., Hottenga, J-J, Pol, H.E.H., Ikeda, M., Ikram, M.K., Jack, C.R., Jenkinson, M., Johnson, R., Jönsson, E.G., Jukema, J.W., Kahn, R.S., Kanai, R., Kloszewska, I., Knopman, D.S., Kochunov, P., Kwok, J.B., Lawrie, S.M., Lemaitre, H., Liu, X., Longo, D.L., Longstreth, W.T., Lopez, O.L., Lovestone, S., Martinez, O.P., Martinot, J-L, Mattay, V.S., McDonald, C., McIntosh, A.M., McMahon, K.L., McMahon, F.J., Mecocci, P., Melle, I., Meyer-Lindenberg, A., Mohnke, S., Montgomery, G.W., Morris, D.W., Mosley, T.H., Mühleisen, T.W., Müller-Myhsok, B., Nalls, M.A., Nauck, M., Nichols, T.E., Niessen, W.J., Nöthen, M.M., Nyberg, L., Ohi, K., Olvera, R.L., Ophoff, R.A., Pandolfo, M., Paus, T., Pausova, Z., Penninx, B.W.J.H., Pike, G.B., Potkin, S.G., Psaty, B.M., Reppermund, S., Rietschel, M., Roffman, J.L., Romanczuk-Seiferth, N., Rotter, J.I., Ryten, M., Sacco, R.L., Sachdev, P.S., Saykin, A.J., Schmidt, R., Schofield, P.R., Sigurdsson, S., Simmons, A., Singleton, A., Sisodiya, S.M., Smith, C., Smoller, J.W., Soininen, H., Srikanth, V., Steen, V.M., Stott, D.J., Sussmann, J.E., Thalamuthu, A., Tiemeier, H., Toga, A.W., Traynor, B.J., Troncoso, J., Turner, J.A., Tzourio, C., Uitterlinden, A.G., Hernández, M.C.V., van der Brug, M., Van der Lugt, A., van der Wee, N.J.A., van Duijn, C.M., van Haren, N.E.M., Van′t Ent, D., van Tol, M-J, Vardarajan, B.N., Veltman, D.J., Vernooij, M.W., Volzke, H., Walter, H., Wardlaw, J.M., Wassink, T.H., Weale, M.E., Weinberger, D.R., Weiner, M.W., Wen, W., Westman, E., White, T., Wong, T.Y., Wright, C.B., Zielke, H.R., Zonderman, A.B., Deary, I.J., DeCarli, C., Schmidt, H., Martin, N.G., de Craen, A.J.M., Wright, M.J., Launer, L.J., Schumann, G., Fornage, M., Franke, B., Debette, S., Medland, S.E., Ikram, M.A., and Thompson, P.M.
Abstract: Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five previously unknown loci for intracranial volume and confirmed two known signals. Four of the loci were also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (ρgenetic = 0.748), which indicates a similar genetic background and allowed us to identify four additional loci through meta-analysis (Ncombined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, and Parkinson's disease, and were enriched near genes involved in growth pathways, including PI3K-AKT signaling. These findings identify the biological underpinnings of intracranial volume and their link to physiological and pathological traits.
Published: 2016

11. Genomic analysis of intracranial and subcortical brain volumes yields polygenic scores accounting for variation across ancestries.

Author: García-Marín LM, Campos AI, Diaz-Torres S, Rabinowitz JA, Ceja Z, Mitchell BL, Grasby KL, Thorp JG, Agartz I, Alhusaini S, Ames D, Amouyel P, Andreassen OA, Arfanakis K, Arias-Vasquez A, Armstrong NJ, Athanasiu L, Bastin ME, Beiser AS, Bennett DA, Bis JC, Boks MPM, Boomsma DI, Brodaty H, Brouwer RM, Buitelaar JK, Burkhardt R, Cahn W, Calhoun VD, Carmichael OT, Chakravarty M, Chen Q, Ching CRK, Cichon S, Crespo-Facorro B, Crivello F, Dale AM, Smith GD, de Geus EJC, De Jager PL, de Zubicaray GI, Debette S, DeCarli C, Depondt C, Desrivières S, Djurovic S, Ehrlich S, Erk S, Espeseth T, Fernández G, Filippi I, Fisher SE, Fleischman DA, Fletcher E, Fornage M, Forstner AJ, Francks C, Franke B, Ge T, Goldman AL, Grabe HJ, Green RC, Grimm O, Groenewold NA, Gruber O, Gudnason V, Håberg AK, Haukvik UK, Heinz A, Hibar DP, Hilal S, Himali JJ, Ho BC, Hoehn DF, Hoekstra PJ, Hofer E, Hoffmann W, Holmes AJ, Homuth G, Hosten N, Ikram MK, Ipser JC, Jack CR Jr, Jahanshad N, Jönsson EG, Kahn RS, Kanai R, Klein M, Knol MJ, Launer LJ, Lawrie SM, Hellard SL, Lee PH, Lemaître H, Li S, Liewald DCM, Lin H, Longstreth WT Jr, Lopez OL, Luciano M, Maillard P, Marquand AF, Martin NG, Martinot JL, Mather KA, Mattay VS, McMahon KL, Mecocci P, Melle I, Meyer-Lindenberg A, Mirza-Schreiber N, Milaneschi Y, Mosley TH, Mühleisen TW, Müller-Myhsok B, Maniega SM, Nauck M, Nho K, Niessen WJ, Nöthen MM, Nyquist PA, Oosterlaan J, Pandolfo M, Paus T, Pausova Z, Penninx BWJH, Pike GB, Psaty BM, Pütz B, Reppermund S, Rietschel MD, Risacher SL, Romanczuk-Seiferth N, Romero-Garcia R, Roshchupkin GV, Rotter JI, Sachdev PS, Sämann PG, Saremi A, Sargurupremraj M, Saykin AJ, Schmaal L, Schmidt H, Schmidt R, Schofield PR, Scholz M, Schumann G, Schwarz E, Shen L, Shin J, Sisodiya SM, Smith AV, Smoller JW, Soininen HS, Steen VM, Stein DJ, Stein JL, Thomopoulos SI, Toga AW, Tordesillas-Gutiérrez D, Trollor JN, Valdes-Hernandez MC, van T Ent D, van Bokhoven H, van der Meer D, van der Wee NJA, Vázquez-Bourgon J, Veltman DJ, Vernooij MW, Villringer A, Vinke LN, Völzke H, Walter H, Wardlaw JM, Weinberger DR, Weiner MW, Wen W, Westlye LT, Westman E, White T, Witte AV, Wolf C, Yang J, Zwiers MP, Ikram MA, Seshadri S, Thompson PM, Satizabal CL, Medland SE, and Rentería ME
Subjects: Humans, Female, Male, Organ Size genetics, Attention Deficit Disorder with Hyperactivity genetics, Attention Deficit Disorder with Hyperactivity pathology, Parkinson Disease genetics, Parkinson Disease pathology, Polymorphism, Single Nucleotide, Genomics methods, Adult, Genetic Predisposition to Disease, Middle Aged, White People genetics, Genome-Wide Association Study, Multifactorial Inheritance genetics, Brain pathology
Abstract: Subcortical brain structures are involved in developmental, psychiatric and neurological disorders. Here we performed genome-wide association studies meta-analyses of intracranial and nine subcortical brain volumes (brainstem, caudate nucleus, putamen, hippocampus, globus pallidus, thalamus, nucleus accumbens, amygdala and the ventral diencephalon) in 74,898 participants of European ancestry. We identified 254 independent loci associated with these brain volumes, explaining up to 35% of phenotypic variance. We observed gene expression in specific neural cell types across differentiation time points, including genes involved in intracellular signaling and brain aging-related processes. Polygenic scores for brain volumes showed predictive ability when applied to individuals of diverse ancestries. We observed causal genetic effects of brain volumes with Parkinson's disease and attention-deficit/hyperactivity disorder. Findings implicate specific gene expression patterns in brain development and genetic variants in comorbid neuropsychiatric disorders, which could point to a brain substrate and region of action for risk genes implicated in brain diseases., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Published: 2024
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12. Next-generation phenotyping integrated in a national framework for patients with ultrarare disorders improves genetic diagnostics and yields new molecular findings.

Author: Schmidt A, Danyel M, Grundmann K, Brunet T, Klinkhammer H, Hsieh TC, Engels H, Peters S, Knaus A, Moosa S, Averdunk L, Boschann F, Sczakiel HL, Schwartzmann S, Mensah MA, Pantel JT, Holtgrewe M, Bösch A, Weiß C, Weinhold N, Suter AA, Stoltenburg C, Neugebauer J, Kallinich T, Kaindl AM, Holzhauer S, Bührer C, Bufler P, Kornak U, Ott CE, Schülke M, Nguyen HHP, Hoffjan S, Grasemann C, Rothoeft T, Brinkmann F, Matar N, Sivalingam S, Perne C, Mangold E, Kreiss M, Cremer K, Betz RC, Mücke M, Grigull L, Klockgether T, Spier I, Heimbach A, Bender T, Brand F, Stieber C, Morawiec AM, Karakostas P, Schäfer VS, Bernsen S, Weydt P, Castro-Gomez S, Aziz A, Grobe-Einsler M, Kimmich O, Kobeleva X, Önder D, Lesmann H, Kumar S, Tacik P, Basin MA, Incardona P, Lee-Kirsch MA, Berner R, Schuetz C, Körholz J, Kretschmer T, Di Donato N, Schröck E, Heinen A, Reuner U, Hanßke AM, Kaiser FJ, Manka E, Munteanu M, Kuechler A, Cordula K, Hirtz R, Schlapakow E, Schlein C, Lisfeld J, Kubisch C, Herget T, Hempel M, Weiler-Normann C, Ullrich K, Schramm C, Rudolph C, Rillig F, Groffmann M, Muntau A, Tibelius A, Schwaibold EMC, Schaaf CP, Zawada M, Kaufmann L, Hinderhofer K, Okun PM, Kotzaeridou U, Hoffmann GF, Choukair D, Bettendorf M, Spielmann M, Ripke A, Pauly M, Münchau A, Lohmann K, Hüning I, Hanker B, Bäumer T, Herzog R, Hellenbroich Y, Westphal DS, Strom T, Kovacs R, Riedhammer KM, Mayerhanser K, Graf E, Brugger M, Hoefele J, Oexle K, Mirza-Schreiber N, Berutti R, Schatz U, Krenn M, Makowski C, Weigand H, Schröder S, Rohlfs M, Vill K, Hauck F, Borggraefe I, Müller-Felber W, Kurth I, Elbracht M, Knopp C, Begemann M, Kraft F, Lemke JR, Hentschel J, Platzer K, Strehlow V, Abou Jamra R, Kehrer M, Demidov G, Beck-Wödl S, Graessner H, Sturm M, Zeltner L, Schöls LJ, Magg J, Bevot A, Kehrer C, Kaiser N, Turro E, Horn D, Grüters-Kieslich A, Klein C, Mundlos S, Nöthen M, Riess O, Meitinger T, Krude H, Krawitz PM, Haack T, Ehmke N, and Wagner M
Subjects: Humans, Female, Male, Child, Germany, Exome Sequencing methods, Adolescent, Genetic Association Studies methods, Genetic Testing methods, Child, Preschool, Prospective Studies, Adult, Neurodevelopmental Disorders genetics, Neurodevelopmental Disorders diagnosis, Infant, Young Adult, Phenotype, High-Throughput Nucleotide Sequencing methods
Abstract: Individuals with ultrarare disorders pose a structural challenge for healthcare systems since expert clinical knowledge is required to establish diagnoses. In TRANSLATE NAMSE, a 3-year prospective study, we evaluated a novel diagnostic concept based on multidisciplinary expertise in Germany. Here we present the systematic investigation of the phenotypic and molecular genetic data of 1,577 patients who had undergone exome sequencing and were partially analyzed with next-generation phenotyping approaches. Molecular genetic diagnoses were established in 32% of the patients totaling 370 distinct molecular genetic causes, most with prevalence below 1:50,000. During the diagnostic process, 34 novel and 23 candidate genotype-phenotype associations were identified, mainly in individuals with neurodevelopmental disorders. Sequencing data of the subcohort that consented to computer-assisted analysis of their facial images with GestaltMatcher could be prioritized more efficiently compared with approaches based solely on clinical features and molecular scores. Our study demonstrates the synergy of using next-generation sequencing and phenotyping for diagnosing ultrarare diseases in routine healthcare and discovering novel etiologies by multidisciplinary teams., (© 2024. The Author(s).)
Published: 2024
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13. Episignature analysis of moderate effects and mosaics.

Author: Oexle K, Zech M, Stühn LG, Siegert S, Brunet T, Schmidt WM, Wagner M, Schmidt A, Engels H, Tilch E, Monestier O, Destrėe A, Hanker B, Boesch S, Jech R, Berutti R, Kaiser F, Haslinger B, Haack TB, Garavaglia B, Krawitz P, Winkelmann J, and Mirza-Schreiber N
Subjects: Humans, Phenotype, Alleles, Mosaicism, DNA Methylation, Abnormalities, Multiple genetics
Abstract: DNA methylation classifiers ("episignatures") help to determine the pathogenicity of variants of uncertain significance (VUS). However, their sensitivity is limited due to their training on unambiguous cases with strong-effect variants so that the classification of variants with reduced effect size or in mosaic state may fail. Moreover, episignature evaluation of mosaics as a function of their degree of mosaicism has not been developed so far. We improved episignatures with respect to three categories. Applying (i) minimum-redundancy-maximum-relevance feature selection we reduced their length by up to one order of magnitude without loss of accuracy. Performing (ii) repeated re-training of a support vector machine classifier by step-wise inclusion of cases in the training set that reached probability scores larger than 0.5, we increased the sensitivity of the episignature-classifiers by 30%. In the newly diagnosed patients we confirmed the association between DNA methylation aberration and age at onset of KMT2B-deficient dystonia. Moreover, we found evidence for allelic series, including KMT2B-variants with moderate effects and comparatively mild phenotypes such as late-onset focal dystonia. Retrained classifiers also can detect mosaics that previously remained below the 0.5-threshold, as we showed for KMT2D-associated Kabuki syndrome. Conversely, episignature-classifiers are able to revoke erroneous exome calls of mosaicism, as we demonstrated by (iii) comparing presumed mosaic cases with a distribution of artificial in silico-mosaics that represented all the possible variation in degree of mosaicism, variant read sampling and methylation analysis., (© 2023. The Author(s).)
Published: 2023
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14. Epigenetic Association Analyses and Risk Prediction of RLS.

Author: Harrer P, Mirza-Schreiber N, Mandel V, Roeber S, Stefani A, Naher S, Wagner M, Gieger C, Waldenberger M, Peters A, Högl B, Herms J, Schormair B, Zhao C, Winkelmann J, and Oexle K
Subjects: Humans, DNA Methylation genetics, DNA, Genome-Wide Association Study methods, Biomarkers, CpG Islands genetics, Epigenesis, Genetic genetics, Restless Legs Syndrome genetics
Abstract: Background: As opposed to other neurobehavioral disorders, epigenetic analyses and biomarkers are largely missing in the case of idiopathic restless legs syndrome (RLS)., Objectives: Our aims were to develop a biomarker for RLS based on DNA methylation in blood and to examine DNA methylation in brain tissues for dissecting RLS pathophysiology., Methods: Methylation of blood DNA from three independent cohorts (n = 2283) and post-mortem brain DNA from two cohorts (n = 61) was assessed by Infinium EPIC 850 K BeadChip. Epigenome-wide association study (EWAS) results of individual cohorts were combined by random-effect meta-analysis. A three-stage selection procedure (discovery, n = 884; testing, n = 520; validation, n = 879) established an epigenetic risk score including 30 CpG sites. Epigenetic age was assessed by Horvath's multi-tissue clock and Shireby's cortical clock., Results: EWAS meta-analysis revealed 149 CpG sites linked to 136 genes (P < 0.05 after Bonferroni correction) in blood and 23 CpG linked to 18 genes in brain (false discovery rate [FDR] < 5%). Gene-set analyses of blood EWAS results suggested enrichments in brain tissue types and in subunits of the kainate-selective glutamate receptor complex. Individual candidate genes of the brain EWAS could be assigned to neurodevelopmental or metabolic traits. The blood epigenetic risk score achieved an area under the curve (AUC) of 0.70 (0.67-0.73) in the validation set, comparable to analogous scores in other neurobehavioral disorders. A significant difference in biological age in blood or brain of RLS patients was not detectable., Conclusions: DNA methylation supports the notion of altered neurodevelopment in RLS. Epigenetic risk scores are reliably associated with RLS but require even higher accuracy to be useful as biomarkers. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)
Published: 2023
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15. Intronic elements associated with insomnia and restless legs syndrome exhibit cell-type-specific epigenetic features contributing to MEIS1 regulation.

Author: Lam DD, Antic Nikolic A, Zhao C, Mirza-Schreiber N, Krężel W, Oexle K, and Winkelmann J
Subjects: Epigenesis, Genetic, Humans, Introns genetics, Myeloid Ecotropic Viral Integration Site 1 Protein genetics, Restless Legs Syndrome genetics, Sleep Initiation and Maintenance Disorders genetics
Abstract: A highly evolutionarily conserved myeloid ecotropic viral integration site 1 (MEIS1) intronic region is strongly associated with restless legs syndrome (RLS) and insomnia. To understand its regulatory function, we dissected the region by analyzing chromatin accessibility, enhancer-promoter contacts, DNA methylation and expression quantitative trait locus (eQTLs) in different human neural cell types and tissues. We observed specific activity with respect to cell type and developmental maturation, indicating a prominent role for distinct highly conserved intronic elements in forebrain inhibitory neuron differentiation. Two elements were hypomethylated in neural cells with higher MEIS1 expression, suggesting a role of enhancer demethylation in gene regulation. MEIS1 eQTLs showed a striking modular chromosomal distribution, with forebrain eQTLs clustering in intron 8/9. Clustered regularly interspersed short palindromic repeats interference targeting of individual elements in this region attenuated MEIS1 expression, revealing a complex regulatory interplay of distinct elements. In summary, we found that MEIS1 regulation is organized in a modular pattern. Disease-associated intronic regulatory elements control MEIS1 expression with cell type and maturation stage specificity, particularly in the inhibitory neuron lineage. The precise spatiotemporal activity of these elements likely contributes to the pathogenesis of insomnia and RLS., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
Published: 2022
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16. Blood DNA methylation provides an accurate biomarker of KMT2B-related dystonia and predicts onset.

Author: Mirza-Schreiber N, Zech M, Wilson R, Brunet T, Wagner M, Jech R, Boesch S, Škorvánek M, Necpál J, Weise D, Weber S, Mollenhauer B, Trenkwalder C, Maier EM, Borggraefe I, Vill K, Hackenberg A, Pilshofer V, Kotzaeridou U, Schwaibold EMC, Hoefele J, Waldenberger M, Gieger C, Peters A, Meitinger T, Schormair B, Winkelmann J, and Oexle K
Subjects: Biomarkers, DNA Methylation genetics, Histone-Lysine N-Methyltransferase genetics, Humans, Mutation, Dystonia genetics, Dystonia therapy, Dystonic Disorders genetics, Dystonic Disorders therapy
Abstract: Dystonia is a prevalent, heterogeneous movement disorder characterized by involuntarily abnormal postures. Biomarkers of dystonia are notoriously lacking. Here, a biomarker is reported for histone lysine methyltransferase (KMT2B)-deficient dystonia, a leading subtype among the individually rare monogenic dystonias. It was derived by applying a support vector machine to an episignature of 113 DNA CpG sites, which, in blood cells, showed significant epigenome-wide association with KMT2B deficiency and at least 1× log-fold change of methylation. This classifier was accurate both when tested on the general population and on samples with various other deficiencies of the epigenetic machinery, thus allowing for definitive evaluation of variants of uncertain significance and identifying patients who may profit from deep brain stimulation, a highly successful treatment in KMT2B-deficient dystonia. Methylation was increased in KMT2B deficiency at all 113 CpG sites. The coefficients of variation of the normalized methylation levels at these sites also perfectly classified the samples with KMT2B-deficient dystonia. Moreover, the mean of the normalized methylation levels correlated well with the age at onset of dystonia (P = 0.003)-being lower in samples with late or incomplete penetrance-thus serving as a predictor of disease onset and severity. Similarly, it may also function in monitoring the recently envisioned treatment of KMT2B deficiency by inhibition of DNA methylation., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
Published: 2022
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17. Cis-epistasis at the LPA locus and risk of cardiovascular diseases.

Author: Zeng L, Moser S, Mirza-Schreiber N, Lamina C, Coassin S, Nelson CP, Annilo T, Franzén O, Kleber ME, Mack S, Andlauer TFM, Jiang B, Stiller B, Li L, Willenborg C, Munz M, Kessler T, Kastrati A, Laugwitz KL, Erdmann J, Moebus S, Nöthen MM, Peters A, Strauch K, Müller-Nurasyid M, Gieger C, Meitinger T, Steinhagen-Thiessen E, März W, Metspalu A, Björkegren JLM, Samani NJ, Kronenberg F, Müller-Myhsok B, and Schunkert H
Subjects: Epistasis, Genetic, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Lipoprotein(a) genetics, Polymorphism, Single Nucleotide, Cardiovascular Diseases diagnosis, Cardiovascular Diseases genetics, Coronary Artery Disease diagnostic imaging, Coronary Artery Disease genetics
Abstract: Aims: Coronary artery disease (CAD) has a strong genetic predisposition. However, despite substantial discoveries made by genome-wide association studies (GWAS), a large proportion of heritability awaits identification. Non-additive genetic effects might be responsible for part of the unaccounted genetic variance. Here, we attempted a proof-of-concept study to identify non-additive genetic effects, namely epistatic interactions, associated with CAD., Methods and Results: We tested for epistatic interactions in 10 CAD case-control studies and UK Biobank with focus on 8068 SNPs at 56 loci with known associations with CAD risk. We identified a SNP pair located in cis at the LPA locus, rs1800769 and rs9458001, to be jointly associated with risk for CAD [odds ratio (OR) = 1.37, P = 1.07 × 10-11], peripheral arterial disease (OR = 1.22, P = 2.32 × 10-4), aortic stenosis (OR = 1.47, P = 6.95 × 10-7), hepatic lipoprotein(a) (Lp(a)) transcript levels (beta = 0.39, P = 1.41 × 10-8), and Lp(a) serum levels (beta = 0.58, P = 8.7 × 10-32), while individual SNPs displayed no association. Further exploration of the LPA locus revealed a strong dependency of these associations on a rare variant, rs140570886, that was previously associated with Lp(a) levels. We confirmed increased CAD risk for heterozygous (relative OR = 1.46, P = 9.97 × 10-32) and individuals homozygous for the minor allele (relative OR = 1.77, P = 0.09) of rs140570886. Using forward model selection, we also show that epistatic interactions between rs140570886, rs9458001, and rs1800769 modulate the effects of the rs140570886 risk allele., Conclusions: These results demonstrate the feasibility of a large-scale knowledge-based epistasis scan and provide rare evidence of an epistatic interaction in a complex human disease. We were directed to a variant (rs140570886) influencing risk through additive genetic as well as epistatic effects. In summary, this study provides deeper insights into the genetic architecture of a locus important for cardiovascular diseases., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)
Published: 2022
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18. GWAS meta-analysis followed by Mendelian randomization revealed potential control mechanisms for circulating α-Klotho levels.

Author: Gergei I, Zheng J, Andlauer TFM, Brandenburg V, Mirza-Schreiber N, Müller-Myhsok B, Krämer BK, Richard D, Falk L, Movérare-Skrtic S, Ohlsson C, Davey Smith G, März W, Voelkl J, and Tobias JH
Subjects: Fibroblast Growth Factors genetics, Fibroblast Growth Factors metabolism, Glucuronidase metabolism, Klotho Proteins, Longitudinal Studies, Phosphates metabolism, Genome-Wide Association Study, Mendelian Randomization Analysis
Abstract: The protein α-Klotho acts as transmembrane co-receptor for fibroblast growth factor 23 (FGF23) and is a key regulator of phosphate homeostasis. However, α-Klotho also exists in a circulating form, with pleiotropic, but incompletely understood functions and regulation. Therefore, we undertook a genome-wide association study (GWAS) meta-analysis followed by Mendelian randomization (MR) of circulating α-Klotho levels. Plasma α-Klotho levels were measured by enzyme-linked immunosorbent assay (ELISA) in the Ludwigshafen Risk and Cardiovascular Health and Avon Longitudinal Study of Parents and Children (mothers) cohorts, followed by a GWAS meta-analysis in 4376 individuals across the two cohorts. Six signals at five loci were associated with circulating α-Klotho levels at genome-wide significance (P < 5 × 10-8), namely ABO, KL, FGFR1, and two post-translational modification genes, B4GALNT3 and CHST9. Together, these loci explained >9% of the variation in circulating α-Klotho levels. MR analyses revealed no causal relationships between α-Klotho and renal function, FGF23-dependent factors such as vitamin D and phosphate levels, or bone mineral density. The screening for genetic correlations with other phenotypes followed by targeted MR suggested causal effects of liability of Crohn's disease risk [Inverse variance weighted (IVW) beta = 0.059 (95% confidence interval 0.026, 0.093)] and low-density lipoprotein cholesterol levels [-0.198 (-0.332, -0.063)] on α-Klotho. Our GWAS findings suggest that two enzymes involved in post-translational modification, B4GALNT3 and CHST9, contribute to genetic influences on α-Klotho levels, presumably by affecting protein turnover and stability. Subsequent evidence from MR analyses on α-Klotho levels suggest regulation by mechanisms besides phosphate-homeostasis and raise the possibility of cross-talk with FGF19- and FGF21-dependent pathways, respectively. Significance statement: α-Klotho as a transmembrane protein is well investigated along the endocrine FGF23-α-Klotho pathway. However, the role of the circulating form of α-Klotho, which is generated by cleavage of transmembrane α-Klotho, remains incompletely understood. Genetic analyses might help to elucidate novel regulatory and functional mechanisms. The identification of genetic factors related to circulating α-Klotho further enables MR to examine causal relationships with other factors. The findings from the first GWAS meta-analysis of circulating α-Klotho levels identified six genome-wide significant signals across five genes. Given the function of two of the genes identified, B4GALNT3 and CHST9, it is tempting to speculate that post-translational modification significantly contributes to genetic influences on α-Klotho levels, presumably by affecting protein turnover and stability., (© The Author(s) 2021. Published by Oxford University Press.)
Published: 2022
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19. Genome-wide association study reveals new insights into the heritability and genetic correlates of developmental dyslexia.

Author: Gialluisi A, Andlauer TFM, Mirza-Schreiber N, Moll K, Becker J, Hoffmann P, Ludwig KU, Czamara D, Pourcain BS, Honbolygó F, Tóth D, Csépe V, Huguet G, Chaix Y, Iannuzzi S, Demonet JF, Morris AP, Hulslander J, Willcutt EG, DeFries JC, Olson RK, Smith SD, Pennington BF, Vaessen A, Maurer U, Lyytinen H, Peyrard-Janvid M, Leppänen PHT, Brandeis D, Bonte M, Stein JF, Talcott JB, Fauchereau F, Wilcke A, Kirsten H, Müller B, Francks C, Bourgeron T, Monaco AP, Ramus F, Landerl K, Kere J, Scerri TS, Paracchini S, Fisher SE, Schumacher J, Nöthen MM, Müller-Myhsok B, and Schulte-Körne G
Subjects: Attention Deficit Disorder with Hyperactivity genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Intracellular Signaling Peptides and Proteins genetics, Dyslexia genetics, Multifactorial Inheritance, Polymorphism, Single Nucleotide
Abstract: Developmental dyslexia (DD) is a learning disorder affecting the ability to read, with a heritability of 40-60%. A notable part of this heritability remains unexplained, and large genetic studies are warranted to identify new susceptibility genes and clarify the genetic bases of dyslexia. We carried out a genome-wide association study (GWAS) on 2274 dyslexia cases and 6272 controls, testing associations at the single variant, gene, and pathway level, and estimating heritability using single-nucleotide polymorphism (SNP) data. We also calculated polygenic scores (PGSs) based on large-scale GWAS data for different neuropsychiatric disorders and cortical brain measures, educational attainment, and fluid intelligence, testing them for association with dyslexia status in our sample. We observed statistically significant (p < 2.8 × 10 -6 ) enrichment of associations at the gene level, for LOC388780 (20p13; uncharacterized gene), and for VEPH1 (3q25), a gene implicated in brain development. We estimated an SNP-based heritability of 20-25% for DD, and observed significant associations of dyslexia risk with PGSs for attention deficit hyperactivity disorder (at p T = 0.05 in the training GWAS: OR = 1.23[1.16; 1.30] per standard deviation increase; p = 8 × 10 -13 ), bipolar disorder (1.53[1.44; 1.63]; p = 1 × 10 -43 ), schizophrenia (1.36[1.28; 1.45]; p = 4 × 10 -22 ), psychiatric cross-disorder susceptibility (1.23[1.16; 1.30]; p = 3 × 10 -12 ), cortical thickness of the transverse temporal gyrus (0.90[0.86; 0.96]; p = 5 × 10 -4 ), educational attainment (0.86[0.82; 0.91]; p = 2 × 10 -7 ), and intelligence (0.72[0.68; 0.76]; p = 9 × 10 -29 ). This study suggests an important contribution of common genetic variants to dyslexia risk, and novel genomic overlaps with psychiatric conditions like bipolar disorder, schizophrenia, and cross-disorder susceptibility. Moreover, it revealed the presence of shared genetic foundations with a neural correlate previously implicated in dyslexia by neuroimaging evidence., (© 2020. The Author(s).)
Published: 2021
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20. The genetic architecture of the human cerebral cortex.

Author: Grasby KL, Jahanshad N, Painter JN, Colodro-Conde L, Bralten J, Hibar DP, Lind PA, Pizzagalli F, Ching CRK, McMahon MAB, Shatokhina N, Zsembik LCP, Thomopoulos SI, Zhu AH, Strike LT, Agartz I, Alhusaini S, Almeida MAA, Alnæs D, Amlien IK, Andersson M, Ard T, Armstrong NJ, Ashley-Koch A, Atkins JR, Bernard M, Brouwer RM, Buimer EEL, Bülow R, Bürger C, Cannon DM, Chakravarty M, Chen Q, Cheung JW, Couvy-Duchesne B, Dale AM, Dalvie S, de Araujo TK, de Zubicaray GI, de Zwarte SMC, den Braber A, Doan NT, Dohm K, Ehrlich S, Engelbrecht HR, Erk S, Fan CC, Fedko IO, Foley SF, Ford JM, Fukunaga M, Garrett ME, Ge T, Giddaluru S, Goldman AL, Green MJ, Groenewold NA, Grotegerd D, Gurholt TP, Gutman BA, Hansell NK, Harris MA, Harrison MB, Haswell CC, Hauser M, Herms S, Heslenfeld DJ, Ho NF, Hoehn D, Hoffmann P, Holleran L, Hoogman M, Hottenga JJ, Ikeda M, Janowitz D, Jansen IE, Jia T, Jockwitz C, Kanai R, Karama S, Kasperaviciute D, Kaufmann T, Kelly S, Kikuchi M, Klein M, Knapp M, Knodt AR, Krämer B, Lam M, Lancaster TM, Lee PH, Lett TA, Lewis LB, Lopes-Cendes I, Luciano M, Macciardi F, Marquand AF, Mathias SR, Melzer TR, Milaneschi Y, Mirza-Schreiber N, Moreira JCV, Mühleisen TW, Müller-Myhsok B, Najt P, Nakahara S, Nho K, Olde Loohuis LM, Orfanos DP, Pearson JF, Pitcher TL, Pütz B, Quidé Y, Ragothaman A, Rashid FM, Reay WR, Redlich R, Reinbold CS, Repple J, Richard G, Riedel BC, Risacher SL, Rocha CS, Mota NR, Salminen L, Saremi A, Saykin AJ, Schlag F, Schmaal L, Schofield PR, Secolin R, Shapland CY, Shen L, Shin J, Shumskaya E, Sønderby IE, Sprooten E, Tansey KE, Teumer A, Thalamuthu A, Tordesillas-Gutiérrez D, Turner JA, Uhlmann A, Vallerga CL, van der Meer D, van Donkelaar MMJ, van Eijk L, van Erp TGM, van Haren NEM, van Rooij D, van Tol MJ, Veldink JH, Verhoef E, Walton E, Wang M, Wang Y, Wardlaw JM, Wen W, Westlye LT, Whelan CD, Witt SH, Wittfeld K, Wolf C, Wolfers T, Wu JQ, Yasuda CL, Zaremba D, Zhang Z, Zwiers MP, Artiges E, Assareh AA, Ayesa-Arriola R, Belger A, Brandt CL, Brown GG, Cichon S, Curran JE, Davies GE, Degenhardt F, Dennis MF, Dietsche B, Djurovic S, Doherty CP, Espiritu R, Garijo D, Gil Y, Gowland PA, Green RC, Häusler AN, Heindel W, Ho BC, Hoffmann WU, Holsboer F, Homuth G, Hosten N, Jack CR Jr, Jang M, Jansen A, Kimbrel NA, Kolskår K, Koops S, Krug A, Lim KO, Luykx JJ, Mathalon DH, Mather KA, Mattay VS, Matthews S, Mayoral Van Son J, McEwen SC, Melle I, Morris DW, Mueller BA, Nauck M, Nordvik JE, Nöthen MM, O'Leary DS, Opel N, Martinot MP, Pike GB, Preda A, Quinlan EB, Rasser PE, Ratnakar V, Reppermund S, Steen VM, Tooney PA, Torres FR, Veltman DJ, Voyvodic JT, Whelan R, White T, Yamamori H, Adams HHH, Bis JC, Debette S, Decarli C, Fornage M, Gudnason V, Hofer E, Ikram MA, Launer L, Longstreth WT, Lopez OL, Mazoyer B, Mosley TH, Roshchupkin GV, Satizabal CL, Schmidt R, Seshadri S, Yang Q, Alvim MKM, Ames D, Anderson TJ, Andreassen OA, Arias-Vasquez A, Bastin ME, Baune BT, Beckham JC, Blangero J, Boomsma DI, Brodaty H, Brunner HG, Buckner RL, Buitelaar JK, Bustillo JR, Cahn W, Cairns MJ, Calhoun V, Carr VJ, Caseras X, Caspers S, Cavalleri GL, Cendes F, Corvin A, Crespo-Facorro B, Dalrymple-Alford JC, Dannlowski U, de Geus EJC, Deary IJ, Delanty N, Depondt C, Desrivières S, Donohoe G, Espeseth T, Fernández G, Fisher SE, Flor H, Forstner AJ, Francks C, Franke B, Glahn DC, Gollub RL, Grabe HJ, Gruber O, Håberg AK, Hariri AR, Hartman CA, Hashimoto R, Heinz A, Henskens FA, Hillegers MHJ, Hoekstra PJ, Holmes AJ, Hong LE, Hopkins WD, Hulshoff Pol HE, Jernigan TL, Jönsson EG, Kahn RS, Kennedy MA, Kircher TTJ, Kochunov P, Kwok JBJ, Le Hellard S, Loughland CM, Martin NG, Martinot JL, McDonald C, McMahon KL, Meyer-Lindenberg A, Michie PT, Morey RA, Mowry B, Nyberg L, Oosterlaan J, Ophoff RA, Pantelis C, Paus T, Pausova Z, Penninx BWJH, Polderman TJC, Posthuma D, Rietschel M, Roffman JL, Rowland LM, Sachdev PS, Sämann PG, Schall U, Schumann G, Scott RJ, Sim K, Sisodiya SM, Smoller JW, Sommer IE, St Pourcain B, Stein DJ, Toga AW, Trollor JN, Van der Wee NJA, van 't Ent D, Völzke H, Walter H, Weber B, Weinberger DR, Wright MJ, Zhou J, Stein JL, Thompson PM, and Medland SE
Subjects: Attention Deficit Disorder with Hyperactivity genetics, Brain Mapping, Cognition, Genetic Loci, Genome-Wide Association Study, Humans, Magnetic Resonance Imaging, Organ Size genetics, Parkinson Disease genetics, Cerebral Cortex anatomy & histology, Genetic Variation
Abstract: The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
Published: 2020
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21. Genetic architecture of subcortical brain structures in 38,851 individuals.

Author: Satizabal CL, Adams HHH, Hibar DP, White CC, Knol MJ, Stein JL, Scholz M, Sargurupremraj M, Jahanshad N, Roshchupkin GV, Smith AV, Bis JC, Jian X, Luciano M, Hofer E, Teumer A, van der Lee SJ, Yang J, Yanek LR, Lee TV, Li S, Hu Y, Koh JY, Eicher JD, Desrivières S, Arias-Vasquez A, Chauhan G, Athanasiu L, Rentería ME, Kim S, Hoehn D, Armstrong NJ, Chen Q, Holmes AJ, den Braber A, Kloszewska I, Andersson M, Espeseth T, Grimm O, Abramovic L, Alhusaini S, Milaneschi Y, Papmeyer M, Axelsson T, Ehrlich S, Roiz-Santiañez R, Kraemer B, Håberg AK, Jones HJ, Pike GB, Stein DJ, Stevens A, Bralten J, Vernooij MW, Harris TB, Filippi I, Witte AV, Guadalupe T, Wittfeld K, Mosley TH, Becker JT, Doan NT, Hagenaars SP, Saba Y, Cuellar-Partida G, Amin N, Hilal S, Nho K, Mirza-Schreiber N, Arfanakis K, Becker DM, Ames D, Goldman AL, Lee PH, Boomsma DI, Lovestone S, Giddaluru S, Le Hellard S, Mattheisen M, Bohlken MM, Kasperaviciute D, Schmaal L, Lawrie SM, Agartz I, Walton E, Tordesillas-Gutierrez D, Davies GE, Shin J, Ipser JC, Vinke LN, Hoogman M, Jia T, Burkhardt R, Klein M, Crivello F, Janowitz D, Carmichael O, Haukvik UK, Aribisala BS, Schmidt H, Strike LT, Cheng CY, Risacher SL, Pütz B, Fleischman DA, Assareh AA, Mattay VS, Buckner RL, Mecocci P, Dale AM, Cichon S, Boks MP, Matarin M, Penninx BWJH, Calhoun VD, Chakravarty MM, Marquand AF, Macare C, Kharabian Masouleh S, Oosterlaan J, Amouyel P, Hegenscheid K, Rotter JI, Schork AJ, Liewald DCM, de Zubicaray GI, Wong TY, Shen L, Sämann PG, Brodaty H, Roffman JL, de Geus EJC, Tsolaki M, Erk S, van Eijk KR, Cavalleri GL, van der Wee NJA, McIntosh AM, Gollub RL, Bulayeva KB, Bernard M, Richards JS, Himali JJ, Loeffler M, Rommelse N, Hoffmann W, Westlye LT, Valdés Hernández MC, Hansell NK, van Erp TGM, Wolf C, Kwok JBJ, Vellas B, Heinz A, Olde Loohuis LM, Delanty N, Ho BC, Ching CRK, Shumskaya E, Singh B, Hofman A, van der Meer D, Homuth G, Psaty BM, Bastin ME, Montgomery GW, Foroud TM, Reppermund S, Hottenga JJ, Simmons A, Meyer-Lindenberg A, Cahn W, Whelan CD, van Donkelaar MMJ, Yang Q, Hosten N, Green RC, Thalamuthu A, Mohnke S, Hulshoff Pol HE, Lin H, Jack CR Jr, Schofield PR, Mühleisen TW, Maillard P, Potkin SG, Wen W, Fletcher E, Toga AW, Gruber O, Huentelman M, Davey Smith G, Launer LJ, Nyberg L, Jönsson EG, Crespo-Facorro B, Koen N, Greve DN, Uitterlinden AG, Weinberger DR, Steen VM, Fedko IO, Groenewold NA, Niessen WJ, Toro R, Tzourio C, Longstreth WT Jr, Ikram MK, Smoller JW, van Tol MJ, Sussmann JE, Paus T, Lemaître H, Schroeter ML, Mazoyer B, Andreassen OA, Holsboer F, Depondt C, Veltman DJ, Turner JA, Pausova Z, Schumann G, van Rooij D, Djurovic S, Deary IJ, McMahon KL, Müller-Myhsok B, Brouwer RM, Soininen H, Pandolfo M, Wassink TH, Cheung JW, Wolfers T, Martinot JL, Zwiers MP, Nauck M, Melle I, Martin NG, Kanai R, Westman E, Kahn RS, Sisodiya SM, White T, Saremi A, van Bokhoven H, Brunner HG, Völzke H, Wright MJ, van 't Ent D, Nöthen MM, Ophoff RA, Buitelaar JK, Fernández G, Sachdev PS, Rietschel M, van Haren NEM, Fisher SE, Beiser AS, Francks C, Saykin AJ, Mather KA, Romanczuk-Seiferth N, Hartman CA, DeStefano AL, Heslenfeld DJ, Weiner MW, Walter H, Hoekstra PJ, Nyquist PA, Franke B, Bennett DA, Grabe HJ, Johnson AD, Chen C, van Duijn CM, Lopez OL, Fornage M, Wardlaw JM, Schmidt R, DeCarli C, De Jager PL, Villringer A, Debette S, Gudnason V, Medland SE, Shulman JM, Thompson PM, Seshadri S, and Ikram MA
Subjects: Adult, Aged, Animals, Cohort Studies, Drosophila melanogaster genetics, Drosophila melanogaster growth & development, Humans, Magnetic Resonance Imaging, Middle Aged, Organ Size, Brain anatomy & histology, Brain metabolism, Drosophila melanogaster metabolism, Genetic Variation, Genome-Wide Association Study, Neurodevelopmental Disorders genetics, Neurodevelopmental Disorders pathology
Abstract: Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.
Published: 2019
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22. Genome-wide association scan identifies new variants associated with a cognitive predictor of dyslexia.

Author: Gialluisi A, Andlauer TFM, Mirza-Schreiber N, Moll K, Becker J, Hoffmann P, Ludwig KU, Czamara D, St Pourcain B, Brandler W, Honbolygó F, Tóth D, Csépe V, Huguet G, Morris AP, Hulslander J, Willcutt EG, DeFries JC, Olson RK, Smith SD, Pennington BF, Vaessen A, Maurer U, Lyytinen H, Peyrard-Janvid M, Leppänen PHT, Brandeis D, Bonte M, Stein JF, Talcott JB, Fauchereau F, Wilcke A, Francks C, Bourgeron T, Monaco AP, Ramus F, Landerl K, Kere J, Scerri TS, Paracchini S, Fisher SE, Schumacher J, Nöthen MM, Müller-Myhsok B, and Schulte-Körne G
Subjects: Adolescent, Adult, Child, Cohort Studies, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Male, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Young Adult, Cognition, Dyslexia genetics, Dyslexia psychology
Abstract: Developmental dyslexia (DD) is one of the most prevalent learning disorders, with high impact on school and psychosocial development and high comorbidity with conditions like attention-deficit hyperactivity disorder (ADHD), depression, and anxiety. DD is characterized by deficits in different cognitive skills, including word reading, spelling, rapid naming, and phonology. To investigate the genetic basis of DD, we conducted a genome-wide association study (GWAS) of these skills within one of the largest studies available, including nine cohorts of reading-impaired and typically developing children of European ancestry (N = 2562-3468). We observed a genome-wide significant effect (p < 1 × 10 -8 ) on rapid automatized naming of letters (RANlet) for variants on 18q12.2, within MIR924HG (micro-RNA 924 host gene; rs17663182 p = 4.73 × 10 -9 ), and a suggestive association on 8q12.3 within NKAIN3 (encoding a cation transporter; rs16928927, p = 2.25 × 10 -8 ). rs17663182 (18q12.2) also showed genome-wide significant multivariate associations with RAN measures (p = 1.15 × 10 -8 ) and with all the cognitive traits tested (p = 3.07 × 10 -8 ), suggesting (relational) pleiotropic effects of this variant. A polygenic risk score (PRS) analysis revealed significant genetic overlaps of some of the DD-related traits with educational attainment (EDUyears) and ADHD. Reading and spelling abilities were positively associated with EDUyears (p ~ [10 -5 -10 -7 ]) and negatively associated with ADHD PRS (p ~ [10 -8 -10 -17 ]). This corroborates a long-standing hypothesis on the partly shared genetic etiology of DD and ADHD, at the genome-wide level. Our findings suggest new candidate DD susceptibility genes and provide new insights into the genetics of dyslexia and its comorbities.
Published: 2019
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23. Genome-wide mapping of genetic determinants influencing DNA methylation and gene expression in human hippocampus.

Author: Schulz H, Ruppert AK, Herms S, Wolf C, Mirza-Schreiber N, Stegle O, Czamara D, Forstner AJ, Sivalingam S, Schoch S, Moebus S, Pütz B, Hillmer A, Fricker N, Vatter H, Müller-Myhsok B, Nöthen MM, Becker AJ, Hoffmann P, Sander T, and Cichon S
Subjects: Adolescent, Adult, Aged, Child, Child, Preschool, Female, Humans, Infant, Male, Middle Aged, Polymorphism, Single Nucleotide, Quantitative Trait Loci genetics, Young Adult, DNA Methylation, Epilepsy, Temporal Lobe genetics, Gene Expression Profiling, Genome-Wide Association Study methods, Hippocampus metabolism
Abstract: Emerging evidence emphasizes the strong impact of regulatory genomic elements in neurodevelopmental processes and the complex pathways of brain disorders. The present genome-wide quantitative trait loci analyses explore the cis-regulatory effects of single-nucleotide polymorphisms (SNPs) on DNA methylation (meQTL) and gene expression (eQTL) in 110 human hippocampal biopsies. We identify cis-meQTLs at 14,118 CpG methylation sites and cis-eQTLs for 302 3'-mRNA transcripts of 288 genes. Hippocampal cis-meQTL-CpGs are enriched in flanking regions of active promoters, CpG island shores, binding sites of the transcription factor CTCF and brain eQTLs. Cis-acting SNPs of hippocampal meQTLs and eQTLs significantly overlap schizophrenia-associated SNPs. Correlations of CpG methylation and RNA expression are found for 34 genes. Our comprehensive maps of cis-acting hippocampal meQTLs and eQTLs provide a link between disease-associated SNPs and the regulatory genome that will improve the functional interpretation of non-coding genetic variants in the molecular genetic dissection of brain disorders.
Published: 2017
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24. Novel genetic loci underlying human intracranial volume identified through genome-wide association.

Author: Adams HH, Hibar DP, Chouraki V, Stein JL, Nyquist PA, Rentería ME, Trompet S, Arias-Vasquez A, Seshadri S, Desrivières S, Beecham AH, Jahanshad N, Wittfeld K, Van der Lee SJ, Abramovic L, Alhusaini S, Amin N, Andersson M, Arfanakis K, Aribisala BS, Armstrong NJ, Athanasiu L, Axelsson T, Beiser A, Bernard M, Bis JC, Blanken LM, Blanton SH, Bohlken MM, Boks MP, Bralten J, Brickman AM, Carmichael O, Chakravarty MM, Chauhan G, Chen Q, Ching CR, Cuellar-Partida G, Braber AD, Doan NT, Ehrlich S, Filippi I, Ge T, Giddaluru S, Goldman AL, Gottesman RF, Greven CU, Grimm O, Griswold ME, Guadalupe T, Hass J, Haukvik UK, Hilal S, Hofer E, Hoehn D, Holmes AJ, Hoogman M, Janowitz D, Jia T, Kasperaviciute D, Kim S, Klein M, Kraemer B, Lee PH, Liao J, Liewald DC, Lopez LM, Luciano M, Macare C, Marquand A, Matarin M, Mather KA, Mattheisen M, Mazoyer B, McKay DR, McWhirter R, Milaneschi Y, Mirza-Schreiber N, Muetzel RL, Maniega SM, Nho K, Nugent AC, Loohuis LM, Oosterlaan J, Papmeyer M, Pappa I, Pirpamer L, Pudas S, Pütz B, Rajan KB, Ramasamy A, Richards JS, Risacher SL, Roiz-Santiañez R, Rommelse N, Rose EJ, Royle NA, Rundek T, Sämann PG, Satizabal CL, Schmaal L, Schork AJ, Shen L, Shin J, Shumskaya E, Smith AV, Sprooten E, Strike LT, Teumer A, Thomson R, Tordesillas-Gutierrez D, Toro R, Trabzuni D, Vaidya D, Van der Grond J, Van der Meer D, Van Donkelaar MM, Van Eijk KR, Van Erp TG, Van Rooij D, Walton E, Westlye LT, Whelan CD, Windham BG, Winkler AM, Woldehawariat G, Wolf C, Wolfers T, Xu B, Yanek LR, Yang J, Zijdenbos A, Zwiers MP, Agartz I, Aggarwal NT, Almasy L, Ames D, Amouyel P, Andreassen OA, Arepalli S, Assareh AA, Barral S, Bastin ME, Becker DM, Becker JT, Bennett DA, Blangero J, van Bokhoven H, Boomsma DI, Brodaty H, Brouwer RM, Brunner HG, Buckner RL, Buitelaar JK, Bulayeva KB, Cahn W, Calhoun VD, Cannon DM, Cavalleri GL, Chen C, Cheng CY, Cichon S, Cookson MR, Corvin A, Crespo-Facorro B, Curran JE, Czisch M, Dale AM, Davies GE, De Geus EJ, De Jager PL, de Zubicaray GI, Delanty N, Depondt C, DeStefano AL, Dillman A, Djurovic S, Donohoe G, Drevets WC, Duggirala R, Dyer TD, Erk S, Espeseth T, Evans DA, Fedko IO, Fernández G, Ferrucci L, Fisher SE, Fleischman DA, Ford I, Foroud TM, Fox PT, Francks C, Fukunaga M, Gibbs JR, Glahn DC, Gollub RL, Göring HH, Grabe HJ, Green RC, Gruber O, Gudnason V, Guelfi S, Hansell NK, Hardy J, Hartman CA, Hashimoto R, Hegenscheid K, Heinz A, Le Hellard S, Hernandez DG, Heslenfeld DJ, Ho BC, Hoekstra PJ, Hoffmann W, Hofman A, Holsboer F, Homuth G, Hosten N, Hottenga JJ, Hulshoff Pol HE, Ikeda M, Ikram MK, Jack CR Jr, Jenkinson M, Johnson R, Jönsson EG, Jukema JW, Kahn RS, Kanai R, Kloszewska I, Knopman DS, Kochunov P, Kwok JB, Lawrie SM, Lemaître H, Liu X, Longo DL, Longstreth WT Jr, Lopez OL, Lovestone S, Martinez O, Martinot JL, Mattay VS, McDonald C, McIntosh AM, McMahon KL, McMahon FJ, Mecocci P, Melle I, Meyer-Lindenberg A, Mohnke S, Montgomery GW, Morris DW, Mosley TH, Mühleisen TW, Müller-Myhsok B, Nalls MA, Nauck M, Nichols TE, Niessen WJ, Nöthen MM, Nyberg L, Ohi K, Olvera RL, Ophoff RA, Pandolfo M, Paus T, Pausova Z, Penninx BW, Pike GB, Potkin SG, Psaty BM, Reppermund S, Rietschel M, Roffman JL, Romanczuk-Seiferth N, Rotter JI, Ryten M, Sacco RL, Sachdev PS, Saykin AJ, Schmidt R, Schofield PR, Sigurdsson S, Simmons A, Singleton A, Sisodiya SM, Smith C, Smoller JW, Soininen H, Srikanth V, Steen VM, Stott DJ, Sussmann JE, Thalamuthu A, Tiemeier H, Toga AW, Traynor BJ, Troncoso J, Turner JA, Tzourio C, Uitterlinden AG, Hernández MC, Van der Brug M, Van der Lugt A, Van der Wee NJ, Van Duijn CM, Van Haren NE, Van T Ent D, Van Tol MJ, Vardarajan BN, Veltman DJ, Vernooij MW, Völzke H, Walter H, Wardlaw JM, Wassink TH, Weale ME, Weinberger DR, Weiner MW, Wen W, Westman E, White T, Wong TY, Wright CB, Zielke HR, Zonderman AB, Deary IJ, DeCarli C, Schmidt H, Martin NG, De Craen AJ, Wright MJ, Launer LJ, Schumann G, Fornage M, Franke B, Debette S, Medland SE, Ikram MA, and Thompson PM
Subjects: Brain growth & development, Brain pathology, Genetic Loci genetics, Humans, Oncogene Protein v-akt genetics, Parkinson Disease genetics, Phenotype, Phosphatidylinositol 3-Kinases genetics, White People, Cognition physiology, Genetic Predisposition to Disease, Genome-Wide Association Study methods, Polymorphism, Single Nucleotide genetics
Abstract: Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five previously unknown loci for intracranial volume and confirmed two known signals. Four of the loci were also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (ρ genetic = 0.748), which indicates a similar genetic background and allowed us to identify four additional loci through meta-analysis (N combined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, and Parkinson's disease, and were enriched near genes involved in growth pathways, including PI3K-AKT signaling. These findings identify the biological underpinnings of intracranial volume and their link to physiological and pathological traits.
Published: 2016
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24 results on '"Mirza-Schreiber, N"'

1. Hypothesis-driven genome-wide association studies provide novel insights into genetics of reading disabilities

2. Genome-wide analyses of individual differences in quantitatively assessed reading- and language-related skills in up to 34,000 people

3. Genome-wide analyses of individual differences in quantitatively assessed reading- and language-related skills in up to 34,000 people

4. Hypothesis-driven genome-wide association studies provide novel insights into genetics of reading disabilities

5. Genome-wide association study reveals new insights into the heritability and genetic correlates of developmental dyslexia

6. The genetic architecture of the human cerebral cortex

7. The genetic architecture of the human cerebral cortex

8. Genetic architecture of subcortical brain structures in 38,851 individuals

9. Genetic architecture of subcortical brain structures in 38,851 individuals

10. Novel genetic loci underlying human intracranial volume identified through genome-wide association

11. Genomic analysis of intracranial and subcortical brain volumes yields polygenic scores accounting for variation across ancestries.

12. Next-generation phenotyping integrated in a national framework for patients with ultrarare disorders improves genetic diagnostics and yields new molecular findings.

13. Episignature analysis of moderate effects and mosaics.

14. Epigenetic Association Analyses and Risk Prediction of RLS.

15. Intronic elements associated with insomnia and restless legs syndrome exhibit cell-type-specific epigenetic features contributing to MEIS1 regulation.

16. Blood DNA methylation provides an accurate biomarker of KMT2B-related dystonia and predicts onset.

17. Cis-epistasis at the LPA locus and risk of cardiovascular diseases.

18. GWAS meta-analysis followed by Mendelian randomization revealed potential control mechanisms for circulating α-Klotho levels.

19. Genome-wide association study reveals new insights into the heritability and genetic correlates of developmental dyslexia.

20. The genetic architecture of the human cerebral cortex.

21. Genetic architecture of subcortical brain structures in 38,851 individuals.

22. Genome-wide association scan identifies new variants associated with a cognitive predictor of dyslexia.

23. Genome-wide mapping of genetic determinants influencing DNA methylation and gene expression in human hippocampus.

24. Novel genetic loci underlying human intracranial volume identified through genome-wide association.

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