Collection of Clinical and Epidemiological Data for Genetic Linkage and Association Studies

Lindsay Farrer1, Mark Logue1

1 Boston University School of Medicine, Boston, Massachusetts
Publication Name:  Current Protocols in Human Genetics
Unit Number:  Unit 1.1
DOI:  10.1002/0471142905.hg0101s72
Online Posting Date:  January, 2012
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Modern gene‐mapping can include linkage studies, which correlate the presence of disease to broad genomic regions in either small or large family units, and association studies, which can narrow the location of a disease‐predisposing trait to a single gene using either case‐control or family data. This unit provides an overview of key concepts and presents guidelines for collecting diagnostic, epidemiological, and genealogical data from potential study participants. The commentary discusses the use of publicly available data from online resources, methods for evaluating evidence of genetic versus environmental influences in a disease or disease‐related endophenotype, and use of e‐forms to capture data electronically. Curr. Protoc. Hum. Genet. 72:1.1.1‐1.1.20 © 2012 by John Wiley & Sons, Inc.

Keywords: genetics and genomics; genetic linkage analysis; genetic association analysis

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Table of Contents

  • Introduction
  • Key Concepts
  • Strategic Approach: Collecting Data for Linkage and Association Studies
  • Commentary
  • Literature Cited
  • Figures
  • Tables
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Literature Cited

   Allen, G., Harvald, B., and Shields, J. 1967. Measures of twin concordance. Acta Genet. Stat. Med. 17:475‐481.
   Almasy, L. and Blangero, J. 1998. Multipoint quantitative‐trait linkage analysis in general pedigrees. Am. J. Hum. Genet. 62:1198‐1211.
   Andreasen, N.C., Grove, W.M., Shapiro, R.W., Keller, M.B., Hirschfeld, R.M., and McDonald‐Scott, P. 1981. Reliability of lifetime diagnosis. A multicenter collaborative perspective. Arch. Gen. Psychiatry 38:400‐405.
   American Psychiatric Association, 2000. Diagnostic and Statistical Manual of Mental Disorders, 4th Edition. Text Revision. American Psychiatric Association, Washington.
   Baraitser, M. 1985. The Genetics of Neurological Disorders. Oxford University Press, New York.
   Bundey, S. 1985. Genetics and Neurology. Churchill Livingston, New York.
   Cloninger, C.R., Kaufmann, C.A., Faraone, S.V., Malaspina, D., Svrakic, D.M., Harkavy‐Friedman, J., Suarez, B.K., Matise, T.C., Shore, D., Lee, H., Hampe, C.L., Wynne, D., Drain, C., Markel, P.D., Zambuto, C.T., Schmitt, K., and Tsuang, M.T. 1998. Genome‐wide search for schizophrenia susceptibility loci: The NIMH Genetics Initiative and Millennium Consortium. Am. J. Med. Genet. 81:275‐281.
   Crowe, F.W. 1964. Axillary freckling as a diagnostic aid in neurofibromatosis. Ann. Intern. Med. 6:11142‐11143.
   DeStefano, A.L., Cupples, L.A., Arnos, K.S., Asher, J.H. Jr., Baldwin, C.T., Blanton, S., Carey, M.L., da Silva, E.O., Friedman, T.B., Greenberg, J., Lalwani, A.K., Milunsky, A., Nance, W.E., Pandya, A., Ramesar, R.S., Read, A.P., Tassabejhi, M., Wilcox, E.R., and Farrer, L.A. 1998. Correlation between Waardenburg syndrome phenotype and genotype in a population of individuals with identified PAX3 mutations. Hum. Genet. 102:499‐506.
   Emery, A.E.H. 1986. Methodology in Medical Genetics: An Introduction to Statistical Methods, 2nd Ed. Churchill Livingston, New York.
   Ertekin‐Taner, N., Graff‐Radford, N., Younkin, L.H., Eckman, C., Baker, M., Adamson, J., Ronald, J., Blangero, J., Hutton, M., and Younkin, S.G. 2000. Linkage of plasma Abeta42 to a quantitative locus on chromosome 10 in late‐onset Alzheimer's disease pedigrees. Science 290:2303‐2304.
   Farrer, L.A. and Conneally, P.M. 1985. A genetic model for age at onset in Huntington disease. Am. J. Hum. Genet. 37:350‐357.
   Farrer, L.A. and Cupples, L.A. 1998. Determining the genetic component of a disease. In Approaches to Gene Mapping Studies in Complex Human Diseases (J.L. Haines and M.A. Pericak‐Vance, eds.) John Wiley & Sons, New York.
   Farrer, L.A., Conneally, P.M., and Yu, P.L. 1984. The natural history of Huntington disease: Possible role of “aging genes”. Am. J. Med. Genet. 18:115‐123.
   Farrer, L.A., Myers, R.H., and Cupples, L.A. 1992. Segregation analysis of total nevus density and estimation of lifetime risk and average onset age of melanoma. Cytogenet. Cell Genet. 59:197‐199.
   Farrer, L.A., Cupples, L.A., Wiater, P., Conneally, P.M., Gusella, J.F., and Myers, R.H. 1993. The normal Huntington disease (HD) allele, or a closely linked gene, influences age at onset of HD. Am. J. Hum. Genet. 53:125‐130.
   Fienman, N.L. and Yakovac, W.C. 1970. Neurofibromatosis in childhood. J. Pediatr. 76:339‐346.
   Glanz, K., Murphy, S., Moylan, J., Evensen, D., and Curb, J.D. 2006. Improving dietary self‐monitoring and adherence with hand‐held computers: A pilot study. Am. J. Health Promot. 20:165‐170.
   Green, R.C., Cupples, L.A., Go, R., Benke, K.S., Edeki, T., Griffith, P.A., Williams, M., Hipps, Y., Graff‐Radford, N., Bachman, D., Farrer, L.A.; MIRAGE Study Group. 2002. Risk of dementia among white and African American relatives of patients with Alzheimer disease. JAMA 287:329‐336.
   Hamilton, C.M., Strader, L.C., Pratt, J.G., Maiese, D., Hendershot, T., Kwok, R.K., Hammond, J.A., Huggins, W., Jackman, D., Pan, H., Nettles, D.S., Beaty, T.H., Farrer, L.A., Kraft, P., Marazita, M.L., Ordovas, J.M., Pato, C.N., Spitz, M.R., Wagener, D., Williams, M., Junkins, H.A., Harlan, W.R., Ramos, E.M., and Haines, J. 2011. The PhenX toolkit: Get the most from your measures. Am. J. Epidemiol. 174:253‐260.
   Kessler, R.C., Andrews, G., Mroczek, D., Ustun, T.B., and Wittchen, H‐U. 1998. The World Health Organization composite international diagnostic interview short form (CIDI‐SF). Int. J. Methods Psychiatr. Res. 7:171‐185.
   Kho, A.N., Pacheco, J.A., Peissig, P.L., Rasmussen, L., Newton, K.M., Weston, N., Crane, P.K., Pathak, J., Chute, C.G., Bielinski, S.J., Kullo, I.J., Li, R., Manolio, T.A., Chisholm, R.L., and Denny, J.C. 2011. Electronic medical records for genetic research: Results of the eMERGE consortium. Sci. Transl. Med. 3:79re1.
   Khoury, M.J., Beaty, T.H., and Cohen, B.H. 1986. Interaction of genetics and epidemiology in the literature. Genet. Epidemiol. 3:269‐277.
   Khoury, M.J., Beaty, T.H., and Cohen, B.H. 1993. Fundamentals of Genetic Epidemiology. Oxford University Press, New York.
   Kohane, I.S. 2011. Using electronic health records to drive discovery in disease genomics. Nat. Rev. Genet. 12:417‐428.
   Kroenke, K. and Spitzer, R.L. 2002. The PHQ‐9: A new depression diagnostic and severity measure. Psychiatr. Ann. 32:509‐521.
   Levy, S.E., Mandell, D.S., and Schultz, R.T. 2009. Autism. Lancet 374:1627‐1638.
   McCarty, C.A., Chisholm, R.L., Chute, C.G., Kullo, I.J., Jarvik, G.P., Larson, E.B., Li, R., Masys, D.R., Ritchie, M.D., Roden, D.M., Struewing, J.P., Wolf, W.A.; eMERGE Team. 2011. The eMERGE Network: A consortium of biorepositories linked to electronic medical records data for conducting genomic studies. BMC Med. Genomics 4:13.
   Myers, A., Holmans, P., Marshall, H., Kwon, J., Meyer, D., Ramic, D., Shears, S., Booth, J., DeVrieze, F.W., Crook, R., Hamshere, M., Abraham, R., Tunstall, N., Rice, F., Carty, S., Lillystone, S., Kehoe, P., Rudrasingham, V., Jones, L., Lovestone, S., Perez‐Tur, J., Williams, J., Owen, M.J., Hardy, J., and Goate, A.M. 2000. Susceptibility locus for Alzheimer's disease on chromosome 10. Science 290:2304‐2305.
   North, K.E., Martin, L.J., Dyer, T., Comuzzie, A.G., Williams, J.T; Framingham Heart Study. 2003. HDL cholesterol in females in the Framingham Heart Study is linked to a region of chromosome 2q. BMC Genet. 4:S98.
   Risch, N. 1990. Linkage strategies for genetically complex traits. I. Multilocus models. Am. J. Hum. Genet. 46:222‐228.
   Ritchie, M.D., Denny, J.C., Crawford, D.C., Ramirez, A.H., Weiner, J.B., Pulley, J.M., Basford, M.A., Brown‐Gentry, K., Balser, J.R., Masys, D.R., Haines, J.L., and Roden, D.M. 2010. Robust replication of genotype‐phenotype associations across multiple diseases in an electronic medical record. Am. J. Hum. Genet. 86:560‐572.
   Rivadeneira, F., Styrkársdottir, U., Estrada, K., Halldórsson, B.V., Hsu, Y.H., Richards, J.B., Zillikens, M.C., Kavvoura, F.K., Amin, N., Aulchenko, Y.S., Cupples, L.A., Deloukas, P., Demissie, S., Grundberg, E., Hofman, A., Kong, A., Karasik, D., van Meurs, J.B., Oostra, B., Pastinen, T., Pols, H.A., Sigurdsson, G., Soranzo, N., Thorleifsson, G., Thorsteinsdottir, U., Williams, F.M., Wilson, S.G., Zhou, Y., Ralston, S.H., van Duijn, C.M., Spector, T., Kiel, D.P., Stefansson, K., Ioannidis, J.P., Uitterlinden, A.G.; Genetic Factors for Osteoporosis (GEFOS) Consortium. 2009. Twenty bone‐mineral‐density loci identified by large‐scale meta‐analysis of genome‐wide association studies. Nat. Genet. 41:1199‐1206.
   Roden, D.M., Pulley, J.M., Basford, M.A., Bernard, G.R., Clayton, E.W., Balser, J.R., and Masys, D.R. 2008. Development of a large‐scale de‐identified DNA biobank to enable personalized medicine. Clin. Pharmacol. Ther. 84:362‐369.
   Rothman, K.J., Greenland, S., and Lash, T.L. 2008. Modern Epidemiology, 3rd Ed. Lippincott Williams & Wilkins, Philadelphia.
   Scheinberg, I.H. and Sternlieb, I. 1984. Wilson's Disease. W.B. Saunders, Philadelphia.
   Shi, J., Levinson, D.F., Duan, J., Sanders, A.R., Zheng, Y., Pe'er, I., Dudbridge, F., Holmans, P.A., Whittemore, A.S., Mowry, B.J., Olincy, A., Amin, F., Cloninger, C.R., Silverman, J.M., Buccola, N.G., Byerley, W.F., Black, D.W., Crowe, R.R., Oksenberg, J.R., Mirel, D.B., Kendler, K.S., Freedman, R., and Gejman, P.V. 2009. Common variants on chromosome 6p22.1 are associated with schizophrenia. Nature 460:753‐757.
   Shirima, K., Mukasa, O., Schellenberg, J.A., Manzi, F., John, D., Mushi, A., Mrisho, M., Tanner, M., Mshinda, H., and Schellenberg, D. 2007. The use of personal digital assistants for data entry at the point of collection in a large household survey in southern Tanzania. Emerg. Themes Epidemiol. 4:5.
   Silverman, J.M., Breitner, J.C., Mohs, R.C., and Davis, K.L. 1986. Reliability of the family history method in genetic studies of Alzheimer's disease and related dementias. Am. J. Psychiatry 143:1279‐1282.
Key References
   Khoury et al., 1993. See above.
  A thorough introduction to genetic approaches to familial aggregation.
   Nussbaum, R.L., McInnes, R.R., and Willard, H.F. 2007. Thompson & Thompson Genetics in Medicine. Saunders Elsevier, Philadelphia.
  Contains excellent description of medical genetics concepts.
   Kohane, 2011. See above.
  A detailed overview of the use of electronic medical records in genetic studies of human disease.
Internet Resources
  URL for Online Mendelian Inheritance in Man (OMIM). McKisick‐Nathans Institute for Genetic Medicine, Johns Hopkins University (Baltimore, Md.) and National Center for Biotechnology Information, National Library of Medicine (Bethesda, Md.).
  URL for data base of Genotypes and Phenotypes (dbGaP),National Center for Biotechnology Information, National Library of Medicine (Bethesda, Md.).
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