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Table of Contents
Vol. 70, No. 2, 2010
Issue release date: July 2010
Section title: Original Paper
Hum Hered 2010;70:141–149
(DOI:10.1159/000313854)

Genetic Differences between Five European Populations

Moskvina V.a · Smith M.a · Ivanov D.a · Blackwood D.b · StClair D.c · Hultman C.d · Toncheva D.e · Gill M.f · Corvin A.f · O’Dushlaine C.f · Morris D.W.f · Wray N.R.g · Sullivan P.h · Pato C.i · Pato M.T.i · Sklar P.j · Purcell S.j · Holmans P.a · O’Donovan M.C.a · Owen M.J.a · Kirov G.a · International Schizophrenia Consortium1
aMRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, bDivision of Psychiatry, School of Molecular and Clinical Medicine, University of Edinburgh, Edinburgh, and cInstitute of Medical Sciences, University of Aberdeen, Aberdeen, UK; dDepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; eDepartment of Medical Genetics, University Hospital Maichin Dom, Sofia, Bulgaria; fNeuropsychiatric Genetics Research Group, Department of Psychiatry and Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland; gQueensland Institute of Medical Research, Brisbane, Qld., Australia; hDepartment of Genetics, University of North Carolina, Chapel Hill, N.C., iDepartment of Psychiatry and the Behavioral Sciences, Franz Alexander Chair in Psychiatry, Keck School of Medicine at USC, Los Angeles, Calif., jBroad Institute of Harvard and MIT, Cambridge, Mass., and Center for Human Genetic Research, Massachusetts General Hospital, Boston, Mass., USA
email Corresponding Author

Abstract

Aims: We sought to examine the magnitude of the differences in SNP allele frequencies between five European populations (Scotland, Ireland, Sweden, Bulgaria and Portugal) and to identify the loci with the greatest differences. Methods: We performed a population-based genome-wide association analysis with Affymetrix 6.0 and 5.0 arrays. We used a 4 degrees of freedom χ2 test to determine the magnitude of stratification for each SNP. We then examined the genes within the most stratified regions, using a highly conservative cutoff of p < 10–45. Results: We found 40,593 SNPs which are genome-wide significantly (p ≤ 10–8) stratified between these populations. The largest differences clustered in gene ontology categories for immunity and pigmentation. Some of the top loci span genes that have already been reported as highly stratified: genes for hair color and pigmentation (HERC2, EXOC2, IRF4), the LCT gene, genes involved in NAD metabolism, and in immunity (HLA and the Toll-like receptor genes TLR10, TLR1, TLR6). However, several genes have not previously been reported as stratified within European populations, indicating that they might also have provided selective advantages: several zinc finger genes, two genes involved in glutathione synthesis or function, and most intriguingly, FOXP2, implicated in speech development. Conclusion: Our analysis demonstrates that many SNPs show genome-wide significant differences within European populations and the magnitude of the differences correlate with the geographical distance. At least some of these differences are due to the selective advantage of polymorphisms within these loci.

© 2010 S. Karger AG, Basel


  

Key Words

  • Population
  • Gene
  • Stratification
  • Pigmentation
  • Immunity

References

  1. Heath SC, Gut IG, Brennan P: Investigation of the fine structure of European populations with applications to disease association studies. Eur J Hum Genet 2008;16:1413–1429.
  2. Lao O, Lu TT, Nothnagel M, Junge O, Freitag-Wolf S, Caliebe A, Balascakova M, Bertranpetit J, Bindoff L, Comas D: Correlation between genetic and geographic structure in Europe. Curr Biol 2008;18:1241–1248.
  3. McEvoy BP, Montgomery GW, McRae AF, Ripatti S, Perola M, Spector TD, Cherkas L, Ahmadi KR, Boomsma D, et al:Geographical structure and differential natural selection among North European populations. Genome Res 2009;19:804–814.
  4. Price AL, Helgason A, Palsson S, Stefansson H, St Clair D, Andreassen OA, Reich D, Kong A, Stefansson K: The impact of divergence time on the nature of population structure: an example from Iceland. PLoS Genet 2009;5:e1000505.
  5. Novembre J, Johnson T, Bryc K, Kutalik Z, Boyko AR, Auton A, Indap A, King KS, Bergmann S, et al: Genes mirror geography within Europe. Nature 2008;456:98–101.
  6. Wellcome Trust Case Control Consortium: Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 2007;447:661–678.
  7. Bauchet M, McEvoy B, Pearson LN, Quillen EE, Sarkisian T, Hovhannesyan K, Deka R, Bradley DG, Shriver MD: Measuring European population stratification with microarray genotype data. Am J Hum Genet 2007;80:948–956.
  8. International Schizophrenia Consortium: Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 2008;455:237–241.
  9. International Schizophrenia Consortium: Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 2009;460:748–752.
  10. Menozzi P, Piazza A, Cavalli-Sforza L: Synthetic maps of human gene frequencies in Europeans. Science 1978;201:786–792.
  11. Wright S: The genetical structure of populations. Nature 1950;166:247–249.
  12. Weir BS: Genetic Data Analysis II: Methods for Discrete Population Genetic Data. Sinauer Associate, 1996, p 167.
  13. Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D: Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 2006;38:904–909.
  14. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MAR, Bender D, Maller J, Sklar P, de Bakker PIW, 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.
  15. Holmans P, Green EK, Pahwa JS, Ferreira MA, Purcell SM, Sklar P, Wellcome Trust Case-Control Consortium, Owen MJ, O’Donovan MC, Craddock N: Gene ontology analysis of GWA study data sets provides insights into the biology of bipolar disorder. Am J Hum Genet 2009;85:13–24.
  16. Sulem P, Gudbjartsson DF, Stacey SN, Helgason A, Rafnar T, Magnusson KP, Manolescu A, Karason A, Palsson A, Thorleifsson G, et al: Genetic determinants of hair, eye and skin pigmentation in Europeans. Nat Genet 2007;39:1443–1452.
  17. Han J, Kraft P, Nan H, Guo Q, Chen C, Qureshi A, Hankinson SE, Hu FB, Duffy DL, Zhao ZZ, et al: A genome-wide association study identifies novel alleles associated with hair color and skin pigmentation. PLoS Genet 2008;16:4.
  18. Gathany AH, Hartge P, Davis S, Cerhan JR, Severson RK, Cozen W, Rothman N, Chanock SJ, Wang SS: Relationship between interferon regulatory factor 4 genetic polymorphisms, measures of sun sensitivity and risk for non-Hodgkin lymphoma. Cancer Causes Control 2009;20:1291–1302.
  19. Sundram U, Harvell JD, Rouse RV, Natkunam Y: Expression of the B-cell proliferation marker MUM1 by melanocytic lesions and comparison with S100, gp100 (HMB45), and MelanA. Mod Pathol 2003;16:802–810.
  20. Stokowski RP, Pant PV, Dadd T, Fereday A, Hinds DA, Jarman C, Filsell W, Ginger RS, Green MR, van der Ouderaa FJ, Cox DR: A genomewide association study of skin pigmentation in a South Asian population. Am J Hum Genet 2007;81:1119–1132.
  21. Branicki W, Brudnik U, Draus-Barini J, Kupiec T, Wojas-Pelc A: Association of the SLC45A2 gene with physiological human hair colour variation. J Hum Genet 2008;53:966–971.
  22. Kelley JL, Swanson WL: Positive selection in the human genome: from genome scans to biological significance. Ann Rev Genomics Hum Genet 2008;9:143–160.
  23. Enattah NS, Jensen TG, Nielsen M, Lewinski R, Kuokkanen M, Rasinpera H, El-Shanti H, Seo JK, Alifrangis M, Khalil IF, et al: Independent introduction of two lactase-persistence alleles into human populations reflects different history of adaptation to milk culture. Am J Hum Genet 2008;82:57–72.
  24. Enard W, Przeworski M, Fisher SE, Lai CS, Wiebe V, Kitano T, Monaco AP, Pääbo S: Molecular evolution of FOXP2, a gene involved in speech and language. Nature 2002;418:869–872.
  25. Krause J, Lalueza-Fox C, Orlando L, Enard W, Green R, Burbano H, Hublin J, Hänni C, Fortea J, de la Rasilla M, et al: The derived FOXP2 variant of modern humans was shared with Neandertals. Curr Biol 2007;17:1908–1912.

  

Author Contacts

Valentina Moskvina and George Kirov
MRC Centre for Neuropsychiatric Genetics and Genomics
Department of Psychological Medicine and Neurology, School of Medicine
Cardiff University, Heath Park, Cardiff CF14 4XN (UK), Tel. +44 292 074 6611 Fax +44 292 068 7068, E-Mail MoskvinaV1@cardiff.ac.uk or Kirov@cardiff.ac.uk

  

Article Information

Received: January 15, 2010
Accepted after revision: April 17, 2010
Published online: July 8, 2010
Number of Print Pages : 9
Number of Figures : 2, Number of Tables : 2, Number of References : 25
Additional supplementary material is available online - Number of Parts : 4

  

Publication Details

Human Heredity (International Journal of Human and Medical Genetics)

Vol. 70, No. 2, Year 2010 (Cover Date: July 2010)

Journal Editor: Devoto M. (Philadelphia, Pa.)
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.

Abstract

Aims: We sought to examine the magnitude of the differences in SNP allele frequencies between five European populations (Scotland, Ireland, Sweden, Bulgaria and Portugal) and to identify the loci with the greatest differences. Methods: We performed a population-based genome-wide association analysis with Affymetrix 6.0 and 5.0 arrays. We used a 4 degrees of freedom χ2 test to determine the magnitude of stratification for each SNP. We then examined the genes within the most stratified regions, using a highly conservative cutoff of p < 10–45. Results: We found 40,593 SNPs which are genome-wide significantly (p ≤ 10–8) stratified between these populations. The largest differences clustered in gene ontology categories for immunity and pigmentation. Some of the top loci span genes that have already been reported as highly stratified: genes for hair color and pigmentation (HERC2, EXOC2, IRF4), the LCT gene, genes involved in NAD metabolism, and in immunity (HLA and the Toll-like receptor genes TLR10, TLR1, TLR6). However, several genes have not previously been reported as stratified within European populations, indicating that they might also have provided selective advantages: several zinc finger genes, two genes involved in glutathione synthesis or function, and most intriguingly, FOXP2, implicated in speech development. Conclusion: Our analysis demonstrates that many SNPs show genome-wide significant differences within European populations and the magnitude of the differences correlate with the geographical distance. At least some of these differences are due to the selective advantage of polymorphisms within these loci.

© 2010 S. Karger AG, Basel


  

Author Contacts

Valentina Moskvina and George Kirov
MRC Centre for Neuropsychiatric Genetics and Genomics
Department of Psychological Medicine and Neurology, School of Medicine
Cardiff University, Heath Park, Cardiff CF14 4XN (UK), Tel. +44 292 074 6611 Fax +44 292 068 7068, E-Mail MoskvinaV1@cardiff.ac.uk or Kirov@cardiff.ac.uk

  

Article Information

Received: January 15, 2010
Accepted after revision: April 17, 2010
Published online: July 8, 2010
Number of Print Pages : 9
Number of Figures : 2, Number of Tables : 2, Number of References : 25
Additional supplementary material is available online - Number of Parts : 4

  

Publication Details

Human Heredity (International Journal of Human and Medical Genetics)

Vol. 70, No. 2, Year 2010 (Cover Date: July 2010)

Journal Editor: Devoto M. (Philadelphia, Pa.)
ISSN: 0001-5652 (Print), eISSN: 1423-0062 (Online)

For additional information: http://www.karger.com/HHE


Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: 1/15/2010
Accepted: 4/17/2010
Published online: 7/8/2010
Issue release date: July 2010

Number of Print Pages: 9
Number of Figures: 2
Number of Tables: 2

ISSN: 0001-5652 (Print)
eISSN: 1423-0062 (Online)

For additional information: http://www.karger.com/HHE


Copyright / Drug Dosage

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.

References

  1. Heath SC, Gut IG, Brennan P: Investigation of the fine structure of European populations with applications to disease association studies. Eur J Hum Genet 2008;16:1413–1429.
  2. Lao O, Lu TT, Nothnagel M, Junge O, Freitag-Wolf S, Caliebe A, Balascakova M, Bertranpetit J, Bindoff L, Comas D: Correlation between genetic and geographic structure in Europe. Curr Biol 2008;18:1241–1248.
  3. McEvoy BP, Montgomery GW, McRae AF, Ripatti S, Perola M, Spector TD, Cherkas L, Ahmadi KR, Boomsma D, et al:Geographical structure and differential natural selection among North European populations. Genome Res 2009;19:804–814.
  4. Price AL, Helgason A, Palsson S, Stefansson H, St Clair D, Andreassen OA, Reich D, Kong A, Stefansson K: The impact of divergence time on the nature of population structure: an example from Iceland. PLoS Genet 2009;5:e1000505.
  5. Novembre J, Johnson T, Bryc K, Kutalik Z, Boyko AR, Auton A, Indap A, King KS, Bergmann S, et al: Genes mirror geography within Europe. Nature 2008;456:98–101.
  6. Wellcome Trust Case Control Consortium: Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 2007;447:661–678.
  7. Bauchet M, McEvoy B, Pearson LN, Quillen EE, Sarkisian T, Hovhannesyan K, Deka R, Bradley DG, Shriver MD: Measuring European population stratification with microarray genotype data. Am J Hum Genet 2007;80:948–956.
  8. International Schizophrenia Consortium: Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 2008;455:237–241.
  9. International Schizophrenia Consortium: Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 2009;460:748–752.
  10. Menozzi P, Piazza A, Cavalli-Sforza L: Synthetic maps of human gene frequencies in Europeans. Science 1978;201:786–792.
  11. Wright S: The genetical structure of populations. Nature 1950;166:247–249.
  12. Weir BS: Genetic Data Analysis II: Methods for Discrete Population Genetic Data. Sinauer Associate, 1996, p 167.
  13. Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D: Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 2006;38:904–909.
  14. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MAR, Bender D, Maller J, Sklar P, de Bakker PIW, 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.
  15. Holmans P, Green EK, Pahwa JS, Ferreira MA, Purcell SM, Sklar P, Wellcome Trust Case-Control Consortium, Owen MJ, O’Donovan MC, Craddock N: Gene ontology analysis of GWA study data sets provides insights into the biology of bipolar disorder. Am J Hum Genet 2009;85:13–24.
  16. Sulem P, Gudbjartsson DF, Stacey SN, Helgason A, Rafnar T, Magnusson KP, Manolescu A, Karason A, Palsson A, Thorleifsson G, et al: Genetic determinants of hair, eye and skin pigmentation in Europeans. Nat Genet 2007;39:1443–1452.
  17. Han J, Kraft P, Nan H, Guo Q, Chen C, Qureshi A, Hankinson SE, Hu FB, Duffy DL, Zhao ZZ, et al: A genome-wide association study identifies novel alleles associated with hair color and skin pigmentation. PLoS Genet 2008;16:4.
  18. Gathany AH, Hartge P, Davis S, Cerhan JR, Severson RK, Cozen W, Rothman N, Chanock SJ, Wang SS: Relationship between interferon regulatory factor 4 genetic polymorphisms, measures of sun sensitivity and risk for non-Hodgkin lymphoma. Cancer Causes Control 2009;20:1291–1302.
  19. Sundram U, Harvell JD, Rouse RV, Natkunam Y: Expression of the B-cell proliferation marker MUM1 by melanocytic lesions and comparison with S100, gp100 (HMB45), and MelanA. Mod Pathol 2003;16:802–810.
  20. Stokowski RP, Pant PV, Dadd T, Fereday A, Hinds DA, Jarman C, Filsell W, Ginger RS, Green MR, van der Ouderaa FJ, Cox DR: A genomewide association study of skin pigmentation in a South Asian population. Am J Hum Genet 2007;81:1119–1132.
  21. Branicki W, Brudnik U, Draus-Barini J, Kupiec T, Wojas-Pelc A: Association of the SLC45A2 gene with physiological human hair colour variation. J Hum Genet 2008;53:966–971.
  22. Kelley JL, Swanson WL: Positive selection in the human genome: from genome scans to biological significance. Ann Rev Genomics Hum Genet 2008;9:143–160.
  23. Enattah NS, Jensen TG, Nielsen M, Lewinski R, Kuokkanen M, Rasinpera H, El-Shanti H, Seo JK, Alifrangis M, Khalil IF, et al: Independent introduction of two lactase-persistence alleles into human populations reflects different history of adaptation to milk culture. Am J Hum Genet 2008;82:57–72.
  24. Enard W, Przeworski M, Fisher SE, Lai CS, Wiebe V, Kitano T, Monaco AP, Pääbo S: Molecular evolution of FOXP2, a gene involved in speech and language. Nature 2002;418:869–872.
  25. Krause J, Lalueza-Fox C, Orlando L, Enard W, Green R, Burbano H, Hublin J, Hänni C, Fortea J, de la Rasilla M, et al: The derived FOXP2 variant of modern humans was shared with Neandertals. Curr Biol 2007;17:1908–1912.