Background: Human skull and brain morphology are strongly influenced by genetic factors, and skull size and shape vary worldwide. However, the relationship between specific brain morphology and genetically-determined ancestry is largely unknown. Methods: We used two independent data sets to characterize variation in skull and brain morphology among individuals of European ancestry. The first data set is a historical sample of 1,170 male skulls with 37 shape measurements drawn from 27 European populations. The second data set includes 626 North American individuals of European ancestry participating in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) with magnetic resonance imaging, height and weight, neurological diagnosis, and genome-wide single nucleotide polymorphism (SNP) data. Results: We found that both skull and brain morphological variation exhibit a population-genetic fingerprint among individuals of European ancestry. This fingerprint shows a Northwest to Southeast gradient, is independent of body size, and involves frontotemporal cortical regions. Conclusion: Our findings are consistent with prior evidence for gene flow in Europe due to historical population movements and indicate that genetic background should be considered in studies seeking to identify genes involved in human cortical development and neuropsychiatric disease.
© 2011 S. Karger AG, Basel
- Biological anthropology
- Genetic drift
- Imaging genomics
- Population genetics
- Panizzon MS, Fennema-Notestine C, Eyler LT, Jernigan TL, Prom-Wormley E, Neale M, Jacobson K, Lyons MJ, Grant MD, Franz CE, Xian H, Tsuang M, Fischl B, Seidman L, Dale A, Kremen WS: Distinct genetic influences on cortical surface area and cortical thickness. Cereb Cortex 2009;19:2728–2735.
- Joyner AH, Roddey JC, Bloss CS, Bakken TE, Rimol LM, Melle I, Agartz I, Djurovic S, Topol EJ, Schork NJ, Andreassen OA, Dale AM: A common MECP2 haplotype associates with reduced cortical surface area in humans in two independent populations. Proc Natl Acad Sci USA 2009;106:15483–15488.
- Rimol LM, Agartz I, Djurovic S, Brown AA, Roddey JC, Kahler AK, Mattingsdal M, Athanasiu L, Joyner AH, Schork NJ, Halgren E, Sundet K, Melle I, Dale AM, Andreassen OA: Sex-dependent association of common variants of microcephaly genes with brain structure. Proc Natl Acad Sci USA 2010;107:384–388.
- Schumann CM, Bloss CS, Barnes CC, Wideman GM, Carper RA, Akshoomoff N, Pierce K, Hagler D, Schork N, Lord C, Courchesne E: Longitudinal magnetic resonance imaging study of cortical development through early childhood in autism. J Neurosci 2010;30:4419–4427.
- Brans R, van Haren N, van Baal G, Schnack H, Kahn R, Pol H: Heritability of changes in brain volume over time in twin pairs discordant for schizophrenia. Arch Gen Psychiatry 2008;65:1259.
- Van Essen DC, Dierker D, Snyder AZ, Raichle ME, Reiss AL, Korenberg J: Symmetry of cortical folding abnormalities in Williams syndrome revealed by surface-based analyses. J Neurosci 2006;26:5470–5483.
- White NS, Alkire MT, Haier RJ: A voxel-based morphometric study of nondemented adults with Down syndrome. Neuroimage 2003;20:393–403.
- Howells WW: Cranial Variation in Man: A Study by Multivariate Analysis of Patterns of Difference among Recent Human Populations. Papers of the Peabody Museum of Archaeology and Ethnology No. 67. Cambridge, MA, Harvard University Press, 1973.
- Manica A, Amos W, Balloux F, Hanihara T: The effect of ancient population bottlenecks on human phenotypic variation. Nature 2007;448:346–348.
- Martínez-Abadías N, González-José R, González-Martín A, Van der Molen S, Talavera A, Hernández P, Hernández M: Phenotypic evolution of human craniofacial morphology after admixture: a geometric morphometrics approach. Am J Phys Anthropol 2006;129:387–398.
- Relethford J: Population-specific deviations of global human craniometric variation from a neutral model. Am J Phys Anthropol 2010;142:105–111.
- Martínez-Abadías N, Paschetta C, de Azevedo S, Esparza M, González-José R: Developmental and genetic constraints on neurocranial globularity: insights from analyses of deformed skulls and quantitative genetics. Evol Biol 2009;36:37–56.
- Hallgrímsson B, Lieberman DE, Liu W, Ford-Hutchinson AF, Jirik FR: Epigenetic interactions and the structure of phenotypic variation in the cranium. Evol Dev 2007;9:76–91.
- Novembre J, Johnson T, Bryc K, Kutalik Z, Boyko AR, Auton A, Indap A, King KS, Bergmann S, Nelson MR, Stephens M, Bustamante CD: Genes mirror geography within Europe. Nature 2008;456:98–101.
- Lao O, Lu TT, Nothnagel M, Junge O, Freitag-Wolf S, Caliebe A, Balascakova M, Bertranpetit J, Bindoff LA, Comas D, Holmlund G, Kouvatsi A, Macek M, Mollet I, Parson W, Palo J, Ploski R, Sajantila A, Tagliabracci A, Gether U, Werge T, Rivadeneira F, Hofman A, Uitterlinden AG, Gieger C, Wichmann HE, Ruther A, Schreiber S, Becker C, Nurnberg P, Nelson MR, Krawczak M, Kayser M: Correlation between genetic and geographic structure in Europe. Curr Biol 2008;18:1241–1248.
- Nothnagel M, Lu TT, Kayser M, Krawczak M: Genomic and geographic distribution of SNP-defined runs of homozygosity in Europeans. Hum Mol Genet 2010;19:2927–2935.
- Sokal RR, Uytterschaut H: Cranial variation in European populations: a spatial autocorrelation study at three time periods. Am J Phys Anthropol 1987;74:21–38.
- Sokal RR, Uytterschaut H, Rosing FW, Schwidetzky I: A classification of European skulls from three time periods. Am J Phys Anthropol 1987;74:1–20.
- Hanihara T, Ishida H: Os incae: variation in frequency in major human population groups. J Anat 2001;198:137–152.
- Hanihara T, Ishida H: Metric dental variation of major human populations. Am J Phys Anthropol 2005;128:287–298.
- Hubbe M, Hanihara T, Harvati K: Climate signatures in the morphological differentiation of worldwide modern human populations. Anat Rec 2009;292:1720–1733.
- R: A Language and Environment for Statistical Computing, version 2.11.1. Vienna, R Foundation for Statistical Computing, 2010.
- Hewitt JE, Legendre P, McArdle BH, Thrush SF, Bellehumeur C, Lawrie SM: Identifying relationships between adult and juvenile bivalves at different spatial scales. J Exp Mar Biol Ecol 1997;216:77–98.
- Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC: Plink: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007;81:559–575.
- Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D: Principal components analysis corrects for stratification in genome-wide association studies. Nature Genet 2006;38:904–909.
- Need AC, Kasperaviciute D, Cirulli ET, Goldstein DB: A genome-wide genetic signature of Jewish ancestry perfectly separates individuals with and without full Jewish ancestry in a large random sample of European Americans. Genome Biol 2009;10:R7.
- Price AL, Butler J, Patterson N, Capelli C, Pascali VL, Scarnicci F, Ruiz-Linares A, Groop L, Saetta AA, Korkolopoulou P, Seligsohn U, Waliszewska A, Schirmer C, Ardlie K, Ramos A, Nemesh J, Arbeitman L, Goldstein DB, Reich D, Hirschhorn JN: Discerning the ancestry of European Americans in genetic association studies. PLoS Genet 2008;4:e236.
- Nelis M, Esko T, Magi R, Zimprich F, Zimprich A, Toncheva D, Karachanak S, Piskackova T, Balascak I, Peltonen L, Jakkula E, Rehnstrom K, Lathrop M, Heath S, Galan P, Schreiber S, Meitinger T, Pfeufer A, Wichmann HE, Melegh B, Polgar N, Toniolo D, Gasparini P, D’Adamo P, Klovins J, Nikitina-Zake L, Kucinskas V, Kasnauskiene J, Lubinski J, Debniak T, Limborska S, Khrunin A, Estivill X, Rabionet R, Marsal S, Julia A, Antonarakis SE, Deutsch S, Borel C, Attar H, Gagnebin M, Macek M, Krawczak M, Remm M, Metspalu A: Genetic structure of Europeans: a view from the North-East. PLoS One 2009;4:e5472.
- Seldin MF, Shigeta R, Villoslada P, Selmi C, Tuomilehto J, Silva G, Belmont JW, Klareskog L, Gregersen PK: European population substructure: clustering of northern and southern populations. PLoS Genet 2006;2:e143.
- Silventoinen K, Sammalisto S, Perola M, Boomsma DI, Cornes BK, Davis C, Dunkel L, De Lange M, Harris JR, Hjelmborg JV, Luciano M, Martin NG, Mortensen J, Nistico L, Pedersen NL, Skytthe A, Spector TD, Stazi MA, Willemsen G, Kaprio J: Heritability of adult body height: a comparative study of twin cohorts in eight countries. Twin Res 2003;6:399–408.
- Menozzi P, Piazza A, Cavalli-Sforza L: Synthetic maps of human gene frequencies in Europeans. Science 1978;201:786–792.
- Fix AG: Gene frequency clines produced by kin-structured founder effects. Hum Biol 1997;69:663–673.
- Pinhasi R, von Cramon-Taubadel N: Craniometric data supports demic diffusion model for the spread of agriculture into Europe. PLoS One 2009;4:e6747.
- Bramanti B, Thomas MG, Haak W, Unterlaender M, Jores P, Tambets K, Antanaitis-Jacobs I, Haidle MN, Jankauskas R, Kind CJ, Lueth F, Terberger T, Hiller J, Matsumura S, Forster P, Burger J: Genetic discontinuity between local hunter-gatherers and central Europe’s first farmers. Science 2009;326:137–140.
- Haak W, Balanovsky O, Sanchez JJ, Koshel S, Zaporozhchenko V, Adler CJ, Der Sarkissian CS, Brandt G, Schwarz C, Nicklisch N, Dresely V, Fritsch B, Balanovska E, Villems R, Meller H, Alt KW, Cooper A: Ancient DNA from European early Neolithic farmers reveals their near eastern affinities. PLoS Biol 2010;8:e1000536.
- Battaglia V, Fornarino S, Al-Zahery N, Olivieri A, Pala M, Myres NM, King RJ, Rootsi S, Marjanovic D, Primorac D: Y-chromosomal evidence of the cultural diffusion of agriculture in southeast Europe. Eur J Hum Genet 2008;17:820–830.
- Zalloua PA, Platt DE, El Sibai M, Khalife J, Makhoul N, Haber M, Xue Y, Izaabel H, Bosch E, Adams SM, Arroyo E, Lopez-Parra AM, Aler M, Picornell A, Ramon M, Jobling MA, Comas D, Bertranpetit J, Wells RS, Tyler-Smith C: Identifying genetic traces of historical expansions: Phoenician footprints in the Mediterranean. Am J Hum Genet 2008;83:633–642.
- Helgason A, Hickey E, Goodacre S, Bosnes V, Stefansson K, Ward R, Sykes B: MtDNA and the islands of the North Atlantic: estimating the proportions of Norse and Gaelic ancestry. Am J Hum Genet 2001;68:723–737.
- Roewer L, Croucher PJ, Willuweit S, Lu TT, Kayser M, Lessig R, de Knijff P, Jobling MA, Tyler-Smith C, Krawczak M: Signature of recent historical events in the European Y-chromosomal STR haplotype distribution. Hum Genet 2005;116:279–291.
- Itan Y, Powell A, Beaumont MA, Burger J, Thomas MG: The origins of lactase persistence in Europe. PLoS Comput Biol 2009;5:e1000491.
- Fix AG: Gene frequency clines in Europe: demic diffusion or natural selection? J Royal Anthropol Inst 1996;2:625–643.
- Atzmon G, Hao L, Pe’er I, Velez C, Pearlman A, Palamara PF, Morrow B, Friedman E, Oddoux C, Burns E, Ostrer H: Abraham’s children in the genome era: major Jewish diaspora populations comprise distinct genetic clusters with shared middle eastern ancestry. Am J Hum Genet 2010;86:850–859.
- Behar DM, Yunusbayev B, Metspalu M, Metspalu E, Rosset S, Parik Jr, Rootsi S, Chaubey G, Kutuev I, Yudkovsky G, Khusnutdinova EK, Balanovsky O, Semino O, Pereira L, Comas D, Gurwitz D, Bonne-Tamir B, Parfitt T, Hammer MF, Skorecki K, Villems R: The genome-wide structure of the Jewish people. Nature 2010;466:238–242.
- Kopelman NM, Stone L, Wang C, Gefel D, Feldman M, Hillel J, Rosenberg N: Genomic microsatellites identify shared Jewish ancestry intermediate between Middle Eastern and European populations. BMC Genet 2009;10:1–14.
- Ruff CB, Trinkaus E, Holliday TW: Body mass and encephalization in Pleistocene homo. Nature 1997;387:173–176.
- Weaver T, Roseman C, Stringer C: Were neandertal and modern human cranial differences produced by natural selection or genetic drift? J Hum Evol 2007;53:135–145.
- Deary IJ, Penke L, Johnson W: The neuroscience of human intelligence differences. Nature Rev Neurosci 2010;11:201–211.
- Beals KL, Smith CL, Dodd SM: Brain size, cranial morphology, climate, and time machines. Curr Anthropol 1984;25:301.
- Gilbert SL, Dobyns WB, Lahn BT: Genetic links between brain development and brain evolution. Nature Rev Genet 2005;6:581–590.
Nicholas J. Schork, PhD
The Scripps Research Institute
The Scripps Translational Science Institute
3344 North Torrey Pines Court, Suite 300, La Jolla, CA 92037 (USA)
Tel. +1 858 554 5705, E-Mail firstname.lastname@example.org
Data used in the preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (www.loni.ucla.edu/ADNI). As such, the investigators within the ADNI contributed to the design and implementation of ADNI or provided data but did not participate in analysis or writing of this report (a complete listing of ADNI investigators is available at www.loni.ucla.edu/ADNI/Collaboration/ADNI_Authorship_list.pdf).
Received: February 22, 2011
Accepted after revision: June 17, 2011
Published online: August 17, 2011
Number of Print Pages : 10
Number of Figures : 4, Number of Tables : 0, Number of References : 49
Additional supplementary material is available online - Number of Parts : 2
Human Heredity (International Journal of Human and Medical Genetics)
Vol. 72, No. 1, Year 2011 (Cover Date: September 2011)
Journal Editor: Devoto M. (Philadelphia, Pa./Rome)
ISSN: 0001-5652 (Print), eISSN: 1423-0062 (Online)
For additional information: http://www.karger.com/HHE
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.