Vol. 58, No. 3-4, 2004
Issue release date: March 2005
Hum Hered 2004;58:131–138
Add to my selection

Defining the Phenotype in Human Genetic Studies: Forward Genetics and Reverse Phenotyping

Schulze T.G.a,b · McMahon F.J.b
aDivision of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany; bGenetic Basis of Mood and Anxiety Disorders, Mood and Anxiety Program, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda,Md., USA
email Corresponding Author

 goto top of outline Key Words

  • Phenotypes
  • Assessment
  • Reliability
  • Validity
  • Covariate

 goto top of outline Abstract

The definition of phenotypes for genetic study is a challenging endeavor. Just as we apply strict quality standards to genotype data, we should expect that phenotypes meet consistently high standards of reproducibility and validity. The methods for achieving accurate phenotype assignment in the research setting – the ‘research diagnosis’ – are different from the methods used in clinical diagnosis in the patient care setting. We evaluate some of the main challenges of phenotype definition in human genetics, and begin to outline a set of standards to which phenotypes used in genetics studies may aspire with the goal of increasing the quality and reproducibility of linkage and association studies. Revisiting the traditional phenotype definitions through a focus on familial components and heritable endophenotypes is a time-honored approach. Reverse phenotyping, where phenotypes are refined based on genetic marker data, may be a promising new approach. The stakes are high, since the success of gene mapping in genetically complex disorders hinges on the ability to delineate the target phenotype with accuracy and precision.

Copyright © 2004 S. Karger AG, Basel

 goto top of outline References
  1. Sydenham T: Medical Observations, ed 3. London 1749.
  2. Rice JP, Saccone NL, Rasmussen E. Definition of the phenotype. Adv Genet 2001;42:69–76.
  3. Narrow WE, Rae DS, Robins LN, Regier DA: Revised prevalence estimates of mental disorders in the United States: using a clinical significance criterion to reconcile 2 surveys’ estimates. Arch Gen Psychiatry 2002;59:115–123.
  4. Regier DA, Kaelber CT, Rae DS, Farmer ME, Knauper B, Kessler RC, Norquist GS: Limitations of diagnostic criteria and assessment instruments for mental disorders. Implications for research and policy. Arch Gen Psychiatry 1998;55:109–115.
  5. Barsky AJ: Forgetting, fabricating, and telescoping: the instability of the medical history. Arch Intern Med 2002;162:981–984.
  6. Switzer GE, Wisniewski SR, Belle SH, Dew MA, Schultz R: Selecting, developing, and evaluating research instruments. Soc Psychiatry Psychiatr Epidemiol 1999;34:399–409.
  7. Gershon ES, Guroff JJ: Information from relatives. Arch Gen Psychiatry 1984;41:173–180.
  8. Orvaschel H, Thompson WD, Belanger A, Prusoff BA, Kidd KK: Comparison of the family history method to direct interview. J Affect Dis 1982;4:49–59.
  9. Leckman JF, Sholomskas D, Thompson WD, Belanger A, Weissman MM: Best estimate of lifetime psychiatric diagnosis: a methodological study. Arch Gen Psychiatry 1982;39:879–883.
  10. Kendell RE: The choice of diagnostic criteria for biological research. Arch Gen Psychiatry 1982;39:1334–1339.
  11. Reisch LM, Fosse JS, Beverly K, Yu O, Barlow WE, Harris EL, Rolnick S, Barton MB, Geiger AM, Herrinton LJ, Greene SM, Fletcher SW, Elmore JG: Training, quality assurance, and assessment of medical record abstraction in a multisite study. Am J Epidemiol 2003;157:546–551.
  12. Andreasen NC: Thought, language, and communication disorders. I. Clinical assessment, definition of terms, and evaluation of their reliability. Arch Gen Psychiatry 1979;36:1315–1321.
  13. Kendell R, Jablensky A: Distinguishing between the validity and utility of psychiatric diagnoses. Am J Psychiatry 2003;160:4–12.
  14. Gottesman II, Gould TD: The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry 2003;160:636–645.
  15. Schuckit MA: Genetics of the risk for alcoholism. Am J Addict 2000;9:103–112.
  16. Hasler G, Drevets WC, Manji HK, Charney DS: Discovering endophenotypes for major depression. Neuropsychopharmacology 2004;29:1765–1781.
  17. Gottesman II, Shields J: A polygenic theory of schizophrenia. Proc Natl Acad Sci USA 1967;58:199–205.
  18. Adler LE, Pachtman E, Franks RD, Pecevich M, Waldo MC, Freedman R: Neurophysiological evidence for a defect in neuronal mechanisms involved in sensory gating in schizophrenia. Biol Psychiatry 1982;17:639–654.
  19. Gorman JM, Goetz RR, Dillon D, Liebowitz MR, Fyer AJ, Davies S, Klein DF: Sodium D-lactate infusion of panic disorder patients. Neuropsychopharmacology 1990;3:181–189.
  20. Porjesz B, Begleiter H, Wang K, Almasy L, Chorlian DB, Stimus AT, Kuperman S, O’Connor SJ, Rohrbaugh J, Bauer LO, Edenberg HJ, Goate A, Rice JP, Reich T: Linkage and linkage disequilibrium mapping of ERP and EEG phenotypes. Biol Psychol 2002;61:229.
  21. Tsuang MT: Defining alternative phenotypes for genetic studies: what can we learn from studies of schizophrenia? Am J Med Genet 2001;105;8–10.
  22. Risch NJ: Searching for genetic determinants in the new millennium. Nature 2000;405:847–856.
  23. Meyers DA, Postma DS, Panhuysen CI, Xu J, Amelung PJ, Levitt RCBER: Evidence for a locus regulating total serum IgE levels mapping to chromosome 5. Genomics 1994;23:464–470.
  24. Poulsen P, Kyvik KO, Vaag A, Beck-Nielsen H: Heritability of type II (non-insulin-dependent) diabetes mellitus and abnormal glucose tolerance-a population-based twin study. Diabetologia 1999;42:139–145.
  25. Deng HW, Mahaney MC, Williams JT, Li J, Conway T, Davies KM, Li JL, Deng H, Recker RR: Relevance of the genes for bone mass variation to susceptibility to osteoporotic fractures and its implications to gene search for complex human diseases. Genet Epidemiol 2002;22:12–25.
  26. Recker RR, Deng HW: Role of genetics in osteoporosis. Endocrine 2002;17:55–66.
  27. Styrkarsdottir U, Cazier JB, Kong A, Rolfsson O, Larsen H, Bjarnadottir E, Johannsdottir VD, Sigurdardottir MS, Bagger Y, Christiansen C, Reynisdottir I, Grant SF, Jonasson K, Frigge ML, Gulcher JR, Sigurdsson G, Stefansson K: Linkage of Osteoporosis to Chromosome 20p12 and Association to BMP2. PLoS Biol 2003;1:E69.
  28. Almasy L, Dyer TD, Blangero J: Bivariate quantitative trait linkage analysis: pleiotropy versus co-incident linkages. Genet Epidemiol 1997;14:953–958.
  29. Johnson GC, Koeleman BP, Todd JA: Limitations of stratifying sib-pair data in common disease linkage studies: an example using chromosome 10p14–10q11 in type 1 diabetes. Am J Med Genet 2002;13:158–166.
  30. Van Den Bogaert A, Schumacher J, Schulze TG, Otte AC, Ohlraun S, Kovalenko S, Becker T, Freudenberg J, Jonsson EG, Mattila-Evenden M, Sedvall GC, Czerski PM, Kapelski P, Hauser J, Maier W, Rietschel M, Propping P, Nothen MM, Cichon S: The DTNBP1 (dysbindin) gene contributes to schizophrenia, depending on family history of the disease. Am J Hum Genet 2003;73:1438–1443.
  31. Leal SM, Ott J: Effects of stratification in the analysis of affected-sib-pair data: benefits and costs. Am J Hum Genet 2000;66:567–575.
  32. Teng J, Risch N: The relative power of family-based and case-control designs for linkage disequilibrium studies of complex human diseases. II. Individual genotyping. Genome Res 1999;9:234–241.
  33. Chen WJ, Faraone SV, Orav EJ, Tsuang MT: Estimating age at onset distributions: the bias from prevalent cases and its impact on risk estimation. Genet Epidemiol 1993;10:43–59.
  34. Lange C, DeMeo D, Silverman EK, Weiss ST, Laird NM: PBAT: tools for family-based association studies. Am J Hum Genet 2004;74:367–369.
  35. Schulze TG, McMahon FJ: Genetic association mapping at the crossroads: which test and why? Overview and practical guidelines. Am J Med Genet 2002;114:1–11.
  36. Greenwood CM, Bull SB: Incorporation of covariates into genome scanning using sib-pair analysis in bipolar affective disorder. Genet Epidemiol 1997;14:635–640.
  37. Rice JP, Rochberg N, Neuman RJ, Saccone NL, Liu KY, Zhang X, Culverhouse R: Covariates in linkage analysis. Genet Epidemiol 1999;17(suppl 1):S691–S695.
  38. Saccone NL, Rochberg N, Neuman RJ, Rice JP: Covariates in linkage analysis using sibling and cousin pairs. Genet Epidemiol 2001;21(suppl 1):S540–S545.
  39. Holmans P: Detecting gene-gene interactions using affected sib pair analysis with covariates. Hum Hered 2002;53:92–102.
  40. Devlin B, Jones BL, Bacanu SA, Roeder K: Mixture models for linkage analysis of affected sibling pairs and covariates. Genet Epidemiol 2002;22:52–65.
  41. Hauser ER, Watanabe RM, Duren WL, Bass MP, Langefeld CD, Boehnke M: Ordered subset analysis in genetic linkage mapping of complex traits. Genet Epidemiol 2004;27:53–63.
  42. Shannon WD, Province MA, Rao DC: Tree-based recursive partitioning methods for subdividing sibpairs into relatively more homogeneous subgroups. Genet Epidemiol 2001;20:293–306.
  43. Lander E, Kruglyak L: Genetic dissection of complex traits: Guidelines for interpreting and reporting linkage results. Nat Genet 1995;11:241–247.
  44. Wilcox MA, Wyszynski DF, Panhuysen CI, Ma Q, Yip A, Farrell J, Farrer LA: Empirically derived phenotypic subgroups – qualitative and quantitative trait analyses. BMC Genet 2003;S15.
  45. Rampersaud E, Allen A, Li YJ, Shao Y, Bass M, Haynes C, Ashley-Koch A, Martin ER, Schmidt S, Hauser ER: Adjusting for covariates on a slippery slope: linkage analysis of change over time. BMC Genet 2003;4(suppl 1):S50.

    External Resources

  46. Sengul H, Barmada MM: Stability of exploratory multivariate data modeling in longitudinal data. BMC Genet 2003;4(suppl 1):S38.

    External Resources

  47. Goldin LR, Camp NJ, Keen KJ, Martin LJ, Moslehi R, Ghosh S, North KE, Wyszynski DF, Blacker D: Analysis of metabolic syndrome phenotypes in Framingham Heart Study families from Genetic Analysis Workshop 13. Genet Epidemiol 2003;25(suppl 1):S78–S89.

    External Resources

  48. Lawlor DA, Ebrahim S, May M, Davey SG: (Mis)use of factor analysis in the study of insulin resistance syndrome. Am J Epidemiol 2004;159:1013–1018.
  49. Winawer MR: Epilepsy genetics. Neurologist 2002;8:133–151.
  50. Potash JB, Zandi PP, Willour VL, Lan TH, Huo Y, Avramopoulos D, Shugart YY, MacKinnon DF, Simpson SG, McMahon FJ, DePaulo JR, Jr., McInnis MG: Suggestive linkage to chromosomal regions 13q31 and 22q12 in families with psychotic bipolar disorder. Am J Psychiatry 2003;160:680–686.
  51. Fisfalen M, Schulze TG, DePaulo JR, DeGroot L, Badner JA, McMahon FJ: Familial variation in episode frequency in bipolar affective disorder. Am J Psychiatry 2004, in press.
  52. Takahashi J, Pinto L, Vitaterna, Hotz M: Forward and reverse genetic approaches to behavior in the mouse. Science 1994;264:1724–1733.
  53. Suarez B, Hampe C, Eerdewegh P: Problems of replicating linkage claims in psychiatry; in Gershon ES, Cloninger CR (eds): Genetic Approaches to Mental Disorders. Washington, American Psychiatric Press, 1994.
  54. Ioannidis JP, Ntzani EE, Trikalinos TA, Contopoulos-Ioannidis DG: Replication validity of genetic association studies. Nat Genet 2001;29:306–309.
  55. Neuman RJ, Saccone NL, Holmans P, Rice JP, Sun L: Clustering methods applied to allele sharing data. Genet Epidemiol 2000;19:S57–S63.

    External Resources

  56. McMahon FJ, Simpson SG, McInnis MG, Badner JA, MacKinnon DF, DePaulo JR: Linkage of bipolar disorder to chromosome 18q and the validity of bipolar II disorder. Arch Gen Psychiatry 2001;58:1025–1031.
  57. Rust KF, Rao JN: Variance estimation for complex surveys using replication techniques. Stat Methods Med Res 1996;5:283–310.

 goto top of outline Author Contacts

Thomas G. Schulze, MD
Division of Genetic Epidemiology in Psychiatry
Central Institute of Mental Health, J5
D–68159 Mannheim (Germany)
Tel. +49 621 1703 6056, Fax +49 621 1703 6055, E-Mail schulze@zi-mannheim.de

 goto top of outline Article Information

‘In writing the history of a disease, every philosophical hypothesis ... should lie in abeyance ... [T]he clear and natural phenomena of the disease should be noted ... accurately, and in all their minuteness; in imitation of the exquisite industry of those painters who represent in their portraits the smallest moles and faintest spots.’

Thomas Sydenham [1]

Number of Print Pages : 8
Number of Figures : 1, Number of Tables : 0, Number of References : 57

 goto top of outline Publication Details

Human Heredity (International Journal of Human and Medical Genetics)

Vol. 58, No. 3-4, Year 2004 (Cover Date: Released March 2005)

Journal Editor: J. Ott, New York, N.Y.
ISSN: 0001–5652 (print), 1423–0062 (Online)

For additional information: http://www.karger.ch/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.