Evidence for an Alzheimer disease susceptibility locus on chromosome 12 and for further locus heterogeneity

Ekaterina Rogaeva, Smita Premkumar, Youqiang Song, Sandro Sorbi, Nicholas Brindle, Andrew Paterson, Ranjan Duara, Georges Levesque, Gang Yu, Masaki Nishimura, Masaki Ikeda, Colleen O'Toole, Toshitaka Kawarai, Ricardo Jorge, Daniel Vilarino, Amalia C. Bruni, Lindsay A. Farrer, Peter H. St. George-Hyslop

Research output: Contribution to journalArticle

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Abstract

Context. - Alzheimer disease (AD) susceptibility genes have been identified on chromosomes 1, 14, 19, and 21, and a recent study has suggested a locus on chromosome 12. Objective. - To confirm or refute the existence of a familial AD susceptibility locus on chromosome 12 in an independent sample of familial AD cases. Design. - Retrospective cohort study. DNA data for 6 chromosome 12 genetic markers were evaluated using parametric lod score and nonparametric linkage methods and linkage heterogeneity tests. The latter include the admixture test of homogeneity in the total group of families and the predivided sample test in families stratified by the presence or absence of an apolipoprotein E (APOE) ε4 allele among affected members. Parametric analyses were repeated assuming autosomal dominant inheritance of AD and either age- and sex-dependent penetrance or zero penetrance for the analysis of unaffected relatives. Setting. - Clinical populations in the continental United States, Canada, Argentina, and Italy. Patients. - Fifty-three white families composed of multiple members affected with AD, from whom DNA samples were obtained from 173 patients with AD whose conditions were diagnosed using established criteria and from 146 nondemented relatives. Main Outcome Measure. - Presence of an APOE ε4 allele among affected family members. Results. - Using parametric methods, no evidence for linkage to the region spanned by the chromosome 12 markers could be detected if familial AD is assumed to arise from the same genetic locus in all 53 families. However, significant evidence for linkage was detected in the presence of locus heterogeneity using the admixture test (odds ratio, 15, 135:1). The estimated proportion of linked families within the 53 families examined varied between 0.40 and 0.65, depending on the genetic model assumed and APOE status. The precise location of the AD gene could not be determined, but includes the entire region suggested previously. Nonparametric linkage analysis confirmed linkage to chromosome 12 with the strongest evidence at D12S96 (P<.001). Conclusions. - Our data provide independent confirmation of the existence of an AD susceptibility locus on chromosome 12 and suggest the existence of AD susceptibility genes on other chromosomes. Screening a larger set of families with additional chromosome markers will be necessary for identifying the chromosome 12 AD gene.

Original languageEnglish (US)
Pages (from-to)614-618
Number of pages5
JournalJournal of the American Medical Association
Volume280
Issue number7
DOIs
StatePublished - Aug 19 1998

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Chromosomes, Human, Pair 12
Disease Susceptibility
Alzheimer Disease
Genetic Markers
Apolipoprotein E4
Penetrance
Genes
Alleles
Lod Score
Chromosomes, Human, Pair 14
Genetic Loci
Chromosomes, Human, Pair 1
Genetic Models
DNA
Argentina
Apolipoproteins E
Italy
Canada
Cohort Studies
Retrospective Studies

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Rogaeva, E., Premkumar, S., Song, Y., Sorbi, S., Brindle, N., Paterson, A., ... St. George-Hyslop, P. H. (1998). Evidence for an Alzheimer disease susceptibility locus on chromosome 12 and for further locus heterogeneity. Journal of the American Medical Association, 280(7), 614-618. https://doi.org/10.1001/jama.280.7.614

Evidence for an Alzheimer disease susceptibility locus on chromosome 12 and for further locus heterogeneity. / Rogaeva, Ekaterina; Premkumar, Smita; Song, Youqiang; Sorbi, Sandro; Brindle, Nicholas; Paterson, Andrew; Duara, Ranjan; Levesque, Georges; Yu, Gang; Nishimura, Masaki; Ikeda, Masaki; O'Toole, Colleen; Kawarai, Toshitaka; Jorge, Ricardo; Vilarino, Daniel; Bruni, Amalia C.; Farrer, Lindsay A.; St. George-Hyslop, Peter H.

In: Journal of the American Medical Association, Vol. 280, No. 7, 19.08.1998, p. 614-618.

Research output: Contribution to journalArticle

Rogaeva, E, Premkumar, S, Song, Y, Sorbi, S, Brindle, N, Paterson, A, Duara, R, Levesque, G, Yu, G, Nishimura, M, Ikeda, M, O'Toole, C, Kawarai, T, Jorge, R, Vilarino, D, Bruni, AC, Farrer, LA & St. George-Hyslop, PH 1998, 'Evidence for an Alzheimer disease susceptibility locus on chromosome 12 and for further locus heterogeneity', Journal of the American Medical Association, vol. 280, no. 7, pp. 614-618. https://doi.org/10.1001/jama.280.7.614
Rogaeva, Ekaterina ; Premkumar, Smita ; Song, Youqiang ; Sorbi, Sandro ; Brindle, Nicholas ; Paterson, Andrew ; Duara, Ranjan ; Levesque, Georges ; Yu, Gang ; Nishimura, Masaki ; Ikeda, Masaki ; O'Toole, Colleen ; Kawarai, Toshitaka ; Jorge, Ricardo ; Vilarino, Daniel ; Bruni, Amalia C. ; Farrer, Lindsay A. ; St. George-Hyslop, Peter H. / Evidence for an Alzheimer disease susceptibility locus on chromosome 12 and for further locus heterogeneity. In: Journal of the American Medical Association. 1998 ; Vol. 280, No. 7. pp. 614-618.
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abstract = "Context. - Alzheimer disease (AD) susceptibility genes have been identified on chromosomes 1, 14, 19, and 21, and a recent study has suggested a locus on chromosome 12. Objective. - To confirm or refute the existence of a familial AD susceptibility locus on chromosome 12 in an independent sample of familial AD cases. Design. - Retrospective cohort study. DNA data for 6 chromosome 12 genetic markers were evaluated using parametric lod score and nonparametric linkage methods and linkage heterogeneity tests. The latter include the admixture test of homogeneity in the total group of families and the predivided sample test in families stratified by the presence or absence of an apolipoprotein E (APOE) ε4 allele among affected members. Parametric analyses were repeated assuming autosomal dominant inheritance of AD and either age- and sex-dependent penetrance or zero penetrance for the analysis of unaffected relatives. Setting. - Clinical populations in the continental United States, Canada, Argentina, and Italy. Patients. - Fifty-three white families composed of multiple members affected with AD, from whom DNA samples were obtained from 173 patients with AD whose conditions were diagnosed using established criteria and from 146 nondemented relatives. Main Outcome Measure. - Presence of an APOE ε4 allele among affected family members. Results. - Using parametric methods, no evidence for linkage to the region spanned by the chromosome 12 markers could be detected if familial AD is assumed to arise from the same genetic locus in all 53 families. However, significant evidence for linkage was detected in the presence of locus heterogeneity using the admixture test (odds ratio, 15, 135:1). The estimated proportion of linked families within the 53 families examined varied between 0.40 and 0.65, depending on the genetic model assumed and APOE status. The precise location of the AD gene could not be determined, but includes the entire region suggested previously. Nonparametric linkage analysis confirmed linkage to chromosome 12 with the strongest evidence at D12S96 (P<.001). Conclusions. - Our data provide independent confirmation of the existence of an AD susceptibility locus on chromosome 12 and suggest the existence of AD susceptibility genes on other chromosomes. Screening a larger set of families with additional chromosome markers will be necessary for identifying the chromosome 12 AD gene.",
author = "Ekaterina Rogaeva and Smita Premkumar and Youqiang Song and Sandro Sorbi and Nicholas Brindle and Andrew Paterson and Ranjan Duara and Georges Levesque and Gang Yu and Masaki Nishimura and Masaki Ikeda and Colleen O'Toole and Toshitaka Kawarai and Ricardo Jorge and Daniel Vilarino and Bruni, {Amalia C.} and Farrer, {Lindsay A.} and {St. George-Hyslop}, {Peter H.}",
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T1 - Evidence for an Alzheimer disease susceptibility locus on chromosome 12 and for further locus heterogeneity

AU - Rogaeva, Ekaterina

AU - Premkumar, Smita

AU - Song, Youqiang

AU - Sorbi, Sandro

AU - Brindle, Nicholas

AU - Paterson, Andrew

AU - Duara, Ranjan

AU - Levesque, Georges

AU - Yu, Gang

AU - Nishimura, Masaki

AU - Ikeda, Masaki

AU - O'Toole, Colleen

AU - Kawarai, Toshitaka

AU - Jorge, Ricardo

AU - Vilarino, Daniel

AU - Bruni, Amalia C.

AU - Farrer, Lindsay A.

AU - St. George-Hyslop, Peter H.

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N2 - Context. - Alzheimer disease (AD) susceptibility genes have been identified on chromosomes 1, 14, 19, and 21, and a recent study has suggested a locus on chromosome 12. Objective. - To confirm or refute the existence of a familial AD susceptibility locus on chromosome 12 in an independent sample of familial AD cases. Design. - Retrospective cohort study. DNA data for 6 chromosome 12 genetic markers were evaluated using parametric lod score and nonparametric linkage methods and linkage heterogeneity tests. The latter include the admixture test of homogeneity in the total group of families and the predivided sample test in families stratified by the presence or absence of an apolipoprotein E (APOE) ε4 allele among affected members. Parametric analyses were repeated assuming autosomal dominant inheritance of AD and either age- and sex-dependent penetrance or zero penetrance for the analysis of unaffected relatives. Setting. - Clinical populations in the continental United States, Canada, Argentina, and Italy. Patients. - Fifty-three white families composed of multiple members affected with AD, from whom DNA samples were obtained from 173 patients with AD whose conditions were diagnosed using established criteria and from 146 nondemented relatives. Main Outcome Measure. - Presence of an APOE ε4 allele among affected family members. Results. - Using parametric methods, no evidence for linkage to the region spanned by the chromosome 12 markers could be detected if familial AD is assumed to arise from the same genetic locus in all 53 families. However, significant evidence for linkage was detected in the presence of locus heterogeneity using the admixture test (odds ratio, 15, 135:1). The estimated proportion of linked families within the 53 families examined varied between 0.40 and 0.65, depending on the genetic model assumed and APOE status. The precise location of the AD gene could not be determined, but includes the entire region suggested previously. Nonparametric linkage analysis confirmed linkage to chromosome 12 with the strongest evidence at D12S96 (P<.001). Conclusions. - Our data provide independent confirmation of the existence of an AD susceptibility locus on chromosome 12 and suggest the existence of AD susceptibility genes on other chromosomes. Screening a larger set of families with additional chromosome markers will be necessary for identifying the chromosome 12 AD gene.

AB - Context. - Alzheimer disease (AD) susceptibility genes have been identified on chromosomes 1, 14, 19, and 21, and a recent study has suggested a locus on chromosome 12. Objective. - To confirm or refute the existence of a familial AD susceptibility locus on chromosome 12 in an independent sample of familial AD cases. Design. - Retrospective cohort study. DNA data for 6 chromosome 12 genetic markers were evaluated using parametric lod score and nonparametric linkage methods and linkage heterogeneity tests. The latter include the admixture test of homogeneity in the total group of families and the predivided sample test in families stratified by the presence or absence of an apolipoprotein E (APOE) ε4 allele among affected members. Parametric analyses were repeated assuming autosomal dominant inheritance of AD and either age- and sex-dependent penetrance or zero penetrance for the analysis of unaffected relatives. Setting. - Clinical populations in the continental United States, Canada, Argentina, and Italy. Patients. - Fifty-three white families composed of multiple members affected with AD, from whom DNA samples were obtained from 173 patients with AD whose conditions were diagnosed using established criteria and from 146 nondemented relatives. Main Outcome Measure. - Presence of an APOE ε4 allele among affected family members. Results. - Using parametric methods, no evidence for linkage to the region spanned by the chromosome 12 markers could be detected if familial AD is assumed to arise from the same genetic locus in all 53 families. However, significant evidence for linkage was detected in the presence of locus heterogeneity using the admixture test (odds ratio, 15, 135:1). The estimated proportion of linked families within the 53 families examined varied between 0.40 and 0.65, depending on the genetic model assumed and APOE status. The precise location of the AD gene could not be determined, but includes the entire region suggested previously. Nonparametric linkage analysis confirmed linkage to chromosome 12 with the strongest evidence at D12S96 (P<.001). Conclusions. - Our data provide independent confirmation of the existence of an AD susceptibility locus on chromosome 12 and suggest the existence of AD susceptibility genes on other chromosomes. Screening a larger set of families with additional chromosome markers will be necessary for identifying the chromosome 12 AD gene.

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