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American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1999 Jun;64(6):1670–1678. doi: 10.1086/302400

Assessing the feasibility of linkage disequilibrium methods for mapping complex traits: an initial screen for bipolar disorder loci on chromosome 18.

M A Escamilla 1, L A McInnes 1, M Spesny 1, V I Reus 1, S K Service 1, N Shimayoshi 1, D J Tyler 1, S Silva 1, J Molina 1, A Gallegos 1, L Meza 1, M L Cruz 1, S Batki 1, S Vinogradov 1, T Neylan 1, J B Nguyen 1, E Fournier 1, C Araya 1, S H Barondes 1, P Leon 1, L A Sandkuijl 1, N B Freimer 1
PMCID: PMC1377910  PMID: 10330354

Abstract

Linkage disequilibrium (LD) analysis has been promoted as a method of mapping disease genes, particularly in isolated populations, but has not yet been used for genome-screening studies of complex disorders. We present results of a study to investigate the feasibility of LD methods for genome screening using a sample of individuals affected with severe bipolar mood disorder (BP-I), from an isolated population of the Costa Rican central valley. Forty-eight patients with BP-I were genotyped for markers spaced at approximately 6-cM intervals across chromosome 18. Chromosome 18 was chosen because a previous genome-screening linkage study of two Costa Rican families had suggested a BP-I locus on this chromosome. Results of the current study suggest that LD methods will be useful for mapping BP-I in a larger sample. The results also support previously reported possible localizations (obtained from a separate collection of patients) of BP-I-susceptibility genes at two distinct sites on this chromosome. Current limitations of LD screening for identifying loci for complex traits are discussed, and recommendations are made for future research with these methods.

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Selected References

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  1. Berrettini W. H., Ferraro T. N., Goldin L. R., Weeks D. E., Detera-Wadleigh S., Nurnberger J. I., Jr, Gershon E. S. Chromosome 18 DNA markers and manic-depressive illness: evidence for a susceptibility gene. Proc Natl Acad Sci U S A. 1994 Jun 21;91(13):5918–5921. doi: 10.1073/pnas.91.13.5918. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Collins F. S., Guyer M. S., Charkravarti A. Variations on a theme: cataloging human DNA sequence variation. Science. 1997 Nov 28;278(5343):1580–1581. doi: 10.1126/science.278.5343.1580. [DOI] [PubMed] [Google Scholar]
  3. Di Rienzo A., Peterson A. C., Garza J. C., Valdes A. M., Slatkin M., Freimer N. B. Mutational processes of simple-sequence repeat loci in human populations. Proc Natl Acad Sci U S A. 1994 Apr 12;91(8):3166–3170. doi: 10.1073/pnas.91.8.3166. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Dib C., Fauré S., Fizames C., Samson D., Drouot N., Vignal A., Millasseau P., Marc S., Hazan J., Seboun E. A comprehensive genetic map of the human genome based on 5,264 microsatellites. Nature. 1996 Mar 14;380(6570):152–154. doi: 10.1038/380152a0. [DOI] [PubMed] [Google Scholar]
  5. Durham L. K., Feingold E. Genome scanning for segments shared identical by descent among distant relatives in isolated populations. Am J Hum Genet. 1997 Oct;61(4):830–842. doi: 10.1086/514891. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Escamilla M. A., Spesny M., Reus V. I., Gallegos A., Meza L., Molina J., Sandkuijl L. A., Fournier E., Leon P. E., Smith L. B. Use of linkage disequilibrium approaches to map genes for bipolar disorder in the Costa Rican population. Am J Med Genet. 1996 May 31;67(3):244–253. doi: 10.1002/(SICI)1096-8628(19960531)67:3<244::AID-AJMG2>3.0.CO;2-N. [DOI] [PubMed] [Google Scholar]
  7. Freimer N. B., Reus V. I., Escamilla M. A., McInnes L. A., Spesny M., Leon P., Service S. K., Smith L. B., Silva S., Rojas E. Genetic mapping using haplotype, association and linkage methods suggests a locus for severe bipolar disorder (BPI) at 18q22-q23. Nat Genet. 1996 Apr;12(4):436–441. doi: 10.1038/ng0496-436. [DOI] [PubMed] [Google Scholar]
  8. Freimer N. B., Reus V. I., Escamilla M., Spesny M., Smith L., Service S., Gallegos A., Meza L., Batki S., Vinogradov S. An approach to investigating linkage for bipolar disorder using large Costa Rican pedigrees. Am J Med Genet. 1996 May 31;67(3):254–263. doi: 10.1002/(SICI)1096-8628(19960531)67:3<254::AID-AJMG3>3.0.CO;2-N. [DOI] [PubMed] [Google Scholar]
  9. Friedman T. B., Liang Y., Weber J. L., Hinnant J. T., Barber T. D., Winata S., Arhya I. N., Asher J. H., Jr A gene for congenital, recessive deafness DFNB3 maps to the pericentromeric region of chromosome 17. Nat Genet. 1995 Jan;9(1):86–91. doi: 10.1038/ng0195-86. [DOI] [PubMed] [Google Scholar]
  10. Genomic survey of bipolar illness in the NIMH genetics initiative pedigrees: a preliminary report. Am J Med Genet. 1997 May 31;74(3):227–237. doi: 10.1002/(sici)1096-8628(19970531)74:3<227::aid-ajmg1>3.0.co;2-n. [DOI] [PubMed] [Google Scholar]
  11. Goldin L. R., Chase G. A. Improvement of the power to detect complex disease genes by regional inference procedures. Genet Epidemiol. 1997;14(6):785–789. doi: 10.1002/(SICI)1098-2272(1997)14:6<785::AID-GEPI37>3.0.CO;2-K. [DOI] [PubMed] [Google Scholar]
  12. Gyapay G., Morissette J., Vignal A., Dib C., Fizames C., Millasseau P., Marc S., Bernardi G., Lathrop M., Weissenbach J. The 1993-94 Généthon human genetic linkage map. Nat Genet. 1994 Jun;7(2 Spec No):246–339. doi: 10.1038/ng0694supp-246. [DOI] [PubMed] [Google Scholar]
  13. Houwen R. H., Baharloo S., Blankenship K., Raeymaekers P., Juyn J., Sandkuijl L. A., Freimer N. B. Genome screening by searching for shared segments: mapping a gene for benign recurrent intrahepatic cholestasis. Nat Genet. 1994 Dec;8(4):380–386. doi: 10.1038/ng1294-380. [DOI] [PubMed] [Google Scholar]
  14. Kruglyak L. What is significant in whole-genome linkage disequilibrium studies? Am J Hum Genet. 1997 Oct;61(4):810–812. doi: 10.1086/514893. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Lander E. S., Schork N. J. Genetic dissection of complex traits. Science. 1994 Sep 30;265(5181):2037–2048. doi: 10.1126/science.8091226. [DOI] [PubMed] [Google Scholar]
  16. Lander E., Kruglyak L. Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet. 1995 Nov;11(3):241–247. doi: 10.1038/ng1195-241. [DOI] [PubMed] [Google Scholar]
  17. McInnes L. A., Escamilla M. A., Service S. K., Reus V. I., Leon P., Silva S., Rojas E., Spesny M., Baharloo S., Blankenship K. A complete genome screen for genes predisposing to severe bipolar disorder in two Costa Rican pedigrees. Proc Natl Acad Sci U S A. 1996 Nov 12;93(23):13060–13065. doi: 10.1073/pnas.93.23.13060. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. McMahon F. J., Hopkins P. J., Xu J., McInnis M. G., Shaw S., Cardon L., Simpson S. G., MacKinnon D. F., Stine O. C., Sherrington R. Linkage of bipolar affective disorder to chromosome 18 markers in a new pedigree series. Am J Hum Genet. 1997 Dec;61(6):1397–1404. doi: 10.1086/301630. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Murray J. C., Buetow K. H., Weber J. L., Ludwigsen S., Scherpbier-Heddema T., Manion F., Quillen J., Sheffield V. C., Sunden S., Duyk G. M. A comprehensive human linkage map with centimorgan density. Cooperative Human Linkage Center (CHLC). Science. 1994 Sep 30;265(5181):2049–2054. doi: 10.1126/science.8091227. [DOI] [PubMed] [Google Scholar]
  20. Newport M. J., Huxley C. M., Huston S., Hawrylowicz C. M., Oostra B. A., Williamson R., Levin M. A mutation in the interferon-gamma-receptor gene and susceptibility to mycobacterial infection. N Engl J Med. 1996 Dec 26;335(26):1941–1949. doi: 10.1056/NEJM199612263352602. [DOI] [PubMed] [Google Scholar]
  21. Puffenberger E. G., Kauffman E. R., Bolk S., Matise T. C., Washington S. S., Angrist M., Weissenbach J., Garver K. L., Mascari M., Ladda R. Identity-by-descent and association mapping of a recessive gene for Hirschsprung disease on human chromosome 13q22. Hum Mol Genet. 1994 Aug;3(8):1217–1225. doi: 10.1093/hmg/3.8.1217. [DOI] [PubMed] [Google Scholar]
  22. Risch N., Botstein D. A manic depressive history. Nat Genet. 1996 Apr;12(4):351–353. doi: 10.1038/ng0496-351. [DOI] [PubMed] [Google Scholar]
  23. Risch N., Merikangas K. The future of genetic studies of complex human diseases. Science. 1996 Sep 13;273(5281):1516–1517. doi: 10.1126/science.273.5281.1516. [DOI] [PubMed] [Google Scholar]
  24. Saborio M. Experience in providing genetic services in Costa Rica. Birth Defects Orig Artic Ser. 1992;28(3):96–102. [PubMed] [Google Scholar]
  25. Shah A. B., Chernov I., Zhang H. T., Ross B. M., Das K., Lutsenko S., Parano E., Pavone L., Evgrafov O., Ivanova-Smolenskaya I. A. Identification and analysis of mutations in the Wilson disease gene (ATP7B): population frequencies, genotype-phenotype correlation, and functional analyses. Am J Hum Genet. 1997 Aug;61(2):317–328. doi: 10.1086/514864. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Spielman R. S., McGinnis R. E., Ewens W. J. Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet. 1993 Mar;52(3):506–516. [PMC free article] [PubMed] [Google Scholar]
  27. Stine O. C., Xu J., Koskela R., McMahon F. J., Gschwend M., Friddle C., Clark C. D., McInnis M. G., Simpson S. G., Breschel T. S. Evidence for linkage of bipolar disorder to chromosome 18 with a parent-of-origin effect. Am J Hum Genet. 1995 Dec;57(6):1384–1394. [PMC free article] [PubMed] [Google Scholar]
  28. Terwilliger J. D. A powerful likelihood method for the analysis of linkage disequilibrium between trait loci and one or more polymorphic marker loci. Am J Hum Genet. 1995 Mar;56(3):777–787. [PMC free article] [PubMed] [Google Scholar]
  29. Uhrhammer N., Lange E., Porras O., Naeim A., Chen X., Sheikhavandi S., Chiplunkar S., Yang L., Dandekar S., Liang T. Sublocalization of an ataxia-telangiectasia gene distal to D11S384 by ancestral haplotyping in Costa Rican families. Am J Hum Genet. 1995 Jul;57(1):103–111. [PMC free article] [PubMed] [Google Scholar]
  30. Yuan B., Vaske D., Weber J. L., Beck J., Sheffield V. C. Improved set of short-tandem-repeat polymorphisms for screening the human genome. Am J Hum Genet. 1997 Feb;60(2):459–460. [PMC free article] [PubMed] [Google Scholar]

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