Linkage studies in familial Alzheimer disease

Evidence for chromosome 19 linkage

M. A. Pericak-Vance, J. L. Bebout, P. C. Gaskell, L. H. Yamaoka, W. Y. Hung, M. J. Alberts, A. P. Walker, R. J. Bartlett, C. A. Haynes, K. A. Welsh, N. L. Earl, A. Heyman, C. M. Clark, A. D. Roses

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Abstract

A genetic component in the etiology of Alzheimer disease (AD) has been supported by indirect evidence for several years, with autosomal dominant inheritance with age-dependent pcnctrancc being suggested to explain the familial aggregation of affecteds. St. George Hyslop et al. reported linkage of familial AD (FAD) in four early-onset families (mean age at onset [M] < 50 years). Subsequent studies have been inconsistent in their results; Goate et al. also reported positive lod scores. However, both Pericak-Vance et al.'s study of a series of mainly late-onset FAD families (M > 60 years) and Schellenberg et al.'s study failed to confirm linkage to chromosome 21 (CH21). These various studies suggest the possibility of genetic heterogeneity, with some families linked to CH21 and others unlocalized. Recently, St. George Hyslop et al. extended their analysis to include additional families. The extended analyses supported their earlier finding of linkage to CH21, while showing strong evidence of heterogeneity between early-onset (M < 65 years) and late-onset (M > 60 years) FAD families. Because our families did not show linkage to CH21, we undertook a genomic search for an additional locus for FAD. Because of both the confounding factor of late age at onset of FAD and the lack of clear evidence of Mendelian transmission in some of our families, we employed the affected-pedigree-member (APM) method of linkage analysis as an initial screen for possible linkage. Using this method, we identified two regions suggesting linkage: the proximal long arm of chromosome 19 (CH19) and the CH21 region of FAD linkage reported by St. George Hyslop et al. Application of standard likelihood (LOD score) analysis to these data support the possibility of an FAD gene located on CH19, particularly in the late-onset FAD families. These data further suggest genetic heterogeneity and delineate this region of CH19 as an area needing additional investigation in FAD.

Original languageEnglish (US)
Pages (from-to)1034-1050
Number of pages17
JournalAmerican Journal of Human Genetics
Volume48
Issue number6
StatePublished - Jun 1991

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Chromosomes, Human, Pair 19
Chromosomes, Human, Pair 21
Alzheimer Disease
Genetic Heterogeneity
Age of Onset
Pedigree
Genes

ASJC Scopus subject areas

  • Genetics

Cite this

Pericak-Vance, M. A., Bebout, J. L., Gaskell, P. C., Yamaoka, L. H., Hung, W. Y., Alberts, M. J., ... Roses, A. D. (1991). Linkage studies in familial Alzheimer disease: Evidence for chromosome 19 linkage. American Journal of Human Genetics, 48(6), 1034-1050.

Linkage studies in familial Alzheimer disease : Evidence for chromosome 19 linkage. / Pericak-Vance, M. A.; Bebout, J. L.; Gaskell, P. C.; Yamaoka, L. H.; Hung, W. Y.; Alberts, M. J.; Walker, A. P.; Bartlett, R. J.; Haynes, C. A.; Welsh, K. A.; Earl, N. L.; Heyman, A.; Clark, C. M.; Roses, A. D.

In: American Journal of Human Genetics, Vol. 48, No. 6, 06.1991, p. 1034-1050.

Research output: Contribution to journalArticle

Pericak-Vance, MA, Bebout, JL, Gaskell, PC, Yamaoka, LH, Hung, WY, Alberts, MJ, Walker, AP, Bartlett, RJ, Haynes, CA, Welsh, KA, Earl, NL, Heyman, A, Clark, CM & Roses, AD 1991, 'Linkage studies in familial Alzheimer disease: Evidence for chromosome 19 linkage', American Journal of Human Genetics, vol. 48, no. 6, pp. 1034-1050.
Pericak-Vance MA, Bebout JL, Gaskell PC, Yamaoka LH, Hung WY, Alberts MJ et al. Linkage studies in familial Alzheimer disease: Evidence for chromosome 19 linkage. American Journal of Human Genetics. 1991 Jun;48(6):1034-1050.
Pericak-Vance, M. A. ; Bebout, J. L. ; Gaskell, P. C. ; Yamaoka, L. H. ; Hung, W. Y. ; Alberts, M. J. ; Walker, A. P. ; Bartlett, R. J. ; Haynes, C. A. ; Welsh, K. A. ; Earl, N. L. ; Heyman, A. ; Clark, C. M. ; Roses, A. D. / Linkage studies in familial Alzheimer disease : Evidence for chromosome 19 linkage. In: American Journal of Human Genetics. 1991 ; Vol. 48, No. 6. pp. 1034-1050.
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abstract = "A genetic component in the etiology of Alzheimer disease (AD) has been supported by indirect evidence for several years, with autosomal dominant inheritance with age-dependent pcnctrancc being suggested to explain the familial aggregation of affecteds. St. George Hyslop et al. reported linkage of familial AD (FAD) in four early-onset families (mean age at onset [M] < 50 years). Subsequent studies have been inconsistent in their results; Goate et al. also reported positive lod scores. However, both Pericak-Vance et al.'s study of a series of mainly late-onset FAD families (M > 60 years) and Schellenberg et al.'s study failed to confirm linkage to chromosome 21 (CH21). These various studies suggest the possibility of genetic heterogeneity, with some families linked to CH21 and others unlocalized. Recently, St. George Hyslop et al. extended their analysis to include additional families. The extended analyses supported their earlier finding of linkage to CH21, while showing strong evidence of heterogeneity between early-onset (M < 65 years) and late-onset (M > 60 years) FAD families. Because our families did not show linkage to CH21, we undertook a genomic search for an additional locus for FAD. Because of both the confounding factor of late age at onset of FAD and the lack of clear evidence of Mendelian transmission in some of our families, we employed the affected-pedigree-member (APM) method of linkage analysis as an initial screen for possible linkage. Using this method, we identified two regions suggesting linkage: the proximal long arm of chromosome 19 (CH19) and the CH21 region of FAD linkage reported by St. George Hyslop et al. Application of standard likelihood (LOD score) analysis to these data support the possibility of an FAD gene located on CH19, particularly in the late-onset FAD families. These data further suggest genetic heterogeneity and delineate this region of CH19 as an area needing additional investigation in FAD.",
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