Mapping of a gene for Parkinson's disease to chromosome 4q21-q23

Science

Volumn 274, Issue 5290, 1996, Pages 1197-1199

  Polymeropoulos, Mihael H ^a   Higgins, Joseph J ^b   Golbe, Lawrence I ^c   Johnson, William G ^c   Ide, Susan E ^a   Di Iorio, Giuseppe ^d   Sanges, Giuseppe ^d   Stenroos, Edward S ^c   Pho, Lana T ^b   Schaffer, Alejandro A ^a   Lazzarini, Alice M ^c   Nussbaum, Robert L ^a   Duvoisin, Roger C ^c  

^a NATIONAL HUMAN GENOME RESEARCH INSTITUTE   (United States)

^b NATIONAL INSTITUTES OF HEALTH   (United States)

^c University of Medicine and Dentistry   (United States)

^d SECOND UNIVERSITY OF NAPLES   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

ALZHEIMER DISEASE; ARTICLE; AUTOSOMAL DOMINANT INHERITANCE; CHROMOSOME 4Q; GENE MAPPING; HUMAN; NERVE DEGENERATION; PARKINSON DISEASE; PHENOTYPE; PRIORITY JOURNAL;

CHROMOSOME MAPPING; CHROMOSOMES, HUMAN, PAIR 4; FEMALE; GENETIC MARKERS; HUMANS; LINKAGE (GENETICS); LOD SCORE; MALE; PARKINSON DISEASE; PEDIGREE; PHENOTYPE;

EID: 10544234193     PISSN: 00368075     EISSN: None     Source Type: Journal    
DOI: 10.1126/science.274.5290.1197     Document Type: Article

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23. Samples were collected upon informed consent prior to all genetic and clinical tests. The kindred originated in the town of Contursi in the Salerno province of southern Italy (11); some members emigrated to the United States, Germany, and other countries. The extended family pedigree consists of 592 members wiih 60 individuals affected by PD (Fig. 1). High molecular weight genomic DNA was isolated from whole-blood lysate as described [G. I. Bell, J. Karam, W. Rutter, Proc. Natl. Acad. Sci. U.S.A. 78, 5979 (1981)]. Genotyping was performed as described [J. M. Gyapay et al., Nature Genet 7, 262 (1994)]. Pair-wise linkage analysis was performed by means of the MLINK program of the FASTLINK package. [G. M. Lathrop, J. M. Lalouel, C. Julier, J. Ott. Proc. Natl. Acad. Sci. U.S.A. 81, 3442 (1984); R. W. Cottingham, R. M. Idury, A. A. Schaffer, Am. J. Hum. Genet. 54, 252 (1984); S. K. Gupta, A. A. Schaffer, A. L. Cox, S. Dwarkadas, W. Zwaenepoel, Comp. Biomed. Res. 28, 116 (1995).] Allele frequencies were used as reported in the Genome Data Base (http://gdbwww.gdb.org) and the Cooperative Human Linkage Consortium (CHLC) database (http:// www.chlc.org). Multipoint analysis was performed with the LINKMAP program of the FASTLINK package. For the multipoint analysis allele frequencies were set to 1/n where n equals the number of alleles observed. In the two-point analysis, lod scores were calculated for both the reported and the 1/n allele frequencies with minimal effect on the maximum lod score observed. Simulations of multipoint analysis in a subset of the pedigree with different allele frequencies similarly indicated no significant effect on the scores calculated. Maximum lod scores as shown were observed for the heterozygote and homozygote disease allele penetrance set to 0.99 which is similar to the PD allele penetrance previously reported ranging from 0.88 to 0.94 (11). All unaffected individuals used in the study were of age above the mean for onset of illness. Disease allele frequency was set to 0.001. Distances and order of genetic markers were set as reported in the CHLC database. Overlapping three point analysis was performed for markers D4S2361, D4S 1647, D4S421, and the PD locus. The 12-allele D4S2380 locus was not included because of prohibitive run time. Multipoint analysis was performed on an IBM SP2 parallel computer and the SGI Challenge machine. Changes have been made in the pedigree shown to protect patient confidentiality.
24. Samples were collected upon informed consent prior to all genetic and clinical tests. The kindred originated in the town of Contursi in the Salerno province of southern Italy (11); some members emigrated to the United States, Germany, and other countries. The extended family pedigree consists of 592 members wiih 60 individuals affected by PD (Fig. 1). High molecular weight genomic DNA was isolated from whole-blood lysate as described [G. I. Bell, J. Karam, W. Rutter, Proc. Natl. Acad. Sci. U.S.A. 78, 5979 (1981)]. Genotyping was performed as described [J. M. Gyapay et al., Nature Genet 7, 262 (1994)]. Pair-wise linkage analysis was performed by means of the MLINK program of the FASTLINK package. [G. M. Lathrop, J. M. Lalouel, C. Julier, J. Ott. Proc. Natl. Acad. Sci. U.S.A. 81, 3442 (1984); R. W. Cottingham, R. M. Idury, A. A. Schaffer, Am. J. Hum. Genet. 54, 252 (1984); S. K. Gupta, A. A. Schaffer, A. L. Cox, S. Dwarkadas, W. Zwaenepoel, Comp. Biomed. Res. 28, 116 (1995).] Allele frequencies were used as reported in the Genome Data Base (http://gdbwww.gdb.org) and the Cooperative Human Linkage Consortium (CHLC) database (http:// www.chlc.org). Multipoint analysis was performed with the LINKMAP program of the FASTLINK package. For the multipoint analysis allele frequencies were set to 1/n where n equals the number of alleles observed. In the two-point analysis, lod scores were calculated for both the reported and the 1/n allele frequencies with minimal effect on the maximum lod score observed. Simulations of multipoint analysis in a subset of the pedigree with different allele frequencies similarly indicated no significant effect on the scores calculated. Maximum lod scores as shown were observed for the heterozygote and homozygote disease allele penetrance set to 0.99 which is similar to the PD allele penetrance previously reported ranging from 0.88 to 0.94 (11). All unaffected individuals used in the study were of age above the mean for onset of illness. Disease allele frequency was set to 0.001. Distances and order of genetic markers were set as reported in the CHLC database. Overlapping three point analysis was performed for markers D4S2361, D4S 1647, D4S421, and the PD locus. The 12-allele D4S2380 locus was not included because of prohibitive run time. Multipoint analysis was performed on an IBM SP2 parallel computer and the SGI Challenge machine. Changes have been made in the pedigree shown to protect patient confidentiality.
25. Samples were collected upon informed consent prior to all genetic and clinical tests. The kindred originated in the town of Contursi in the Salerno province of southern Italy (11); some members emigrated to the United States, Germany, and other countries. The extended family pedigree consists of 592 members wiih 60 individuals affected by PD (Fig. 1). High molecular weight genomic DNA was isolated from whole-blood lysate as described [G. I. Bell, J. Karam, W. Rutter, Proc. Natl. Acad. Sci. U.S.A. 78, 5979 (1981)]. Genotyping was performed as described [J. M. Gyapay et al., Nature Genet 7, 262 (1994)]. Pair-wise linkage analysis was performed by means of the MLINK program of the FASTLINK package. [G. M. Lathrop, J. M. Lalouel, C. Julier, J. Ott. Proc. Natl. Acad. Sci. U.S.A. 81, 3442 (1984); R. W. Cottingham, R. M. Idury, A. A. Schaffer, Am. J. Hum. Genet. 54, 252 (1984); S. K. Gupta, A. A. Schaffer, A. L. Cox, S. Dwarkadas, W. Zwaenepoel, Comp. Biomed. Res. 28, 116 (1995).] Allele frequencies were used as reported in the Genome Data Base (http://gdbwww.gdb.org) and the Cooperative Human Linkage Consortium (CHLC) database (http:// www.chlc.org). Multipoint analysis was performed with the LINKMAP program of the FASTLINK package. For the multipoint analysis allele frequencies were set to 1/n where n equals the number of alleles observed. In the two-point analysis, lod scores were calculated for both the reported and the 1/n allele frequencies with minimal effect on the maximum lod score observed. Simulations of multipoint analysis in a subset of the pedigree with different allele frequencies similarly indicated no significant effect on the scores calculated. Maximum lod scores as shown were observed for the heterozygote and homozygote disease allele penetrance set to 0.99 which is similar to the PD allele penetrance previously reported ranging from 0.88 to 0.94 (11). All unaffected individuals used in the study were of age above the mean for onset of illness. Disease allele frequency was set to 0.001. Distances and order of genetic markers were set as reported in the CHLC database. Overlapping three point analysis was performed for markers D4S2361, D4S 1647, D4S421, and the PD locus. The 12-allele D4S2380 locus was not included because of prohibitive run time. Multipoint analysis was performed on an IBM SP2 parallel computer and the SGI Challenge machine. Changes have been made in the pedigree shown to protect patient confidentiality.
26. Samples were collected upon informed consent prior to all genetic and clinical tests. The kindred originated in the town of Contursi in the Salerno province of southern Italy (11); some members emigrated to the United States, Germany, and other countries. The extended family pedigree consists of 592 members wiih 60 individuals affected by PD (Fig. 1). High molecular weight genomic DNA was isolated from whole-blood lysate as described [G. I. Bell, J. Karam, W. Rutter, Proc. Natl. Acad. Sci. U.S.A. 78, 5979 (1981)]. Genotyping was performed as described [J. M. Gyapay et al., Nature Genet 7, 262 (1994)]. Pair-wise linkage analysis was performed by means of the MLINK program of the FASTLINK package. [G. M. Lathrop, J. M. Lalouel, C. Julier, J. Ott. Proc. Natl. Acad. Sci. U.S.A. 81, 3442 (1984); R. W. Cottingham, R. M. Idury, A. A. Schaffer, Am. J. Hum. Genet. 54, 252 (1984); S. K. Gupta, A. A. Schaffer, A. L. Cox, S. Dwarkadas, W. Zwaenepoel, Comp. Biomed. Res. 28, 116 (1995).] Allele frequencies were used as reported in the Genome Data Base (http://gdbwww.gdb.org) and the Cooperative Human Linkage Consortium (CHLC) database (http:// www.chlc.org). Multipoint analysis was performed with the LINKMAP program of the FASTLINK package. For the multipoint analysis allele frequencies were set to 1/n where n equals the number of alleles observed. In the two-point analysis, lod scores were calculated for both the reported and the 1/n allele frequencies with minimal effect on the maximum lod score observed. Simulations of multipoint analysis in a subset of the pedigree with different allele frequencies similarly indicated no significant effect on the scores calculated. Maximum lod scores as shown were observed for the heterozygote and homozygote disease allele penetrance set to 0.99 which is similar to the PD allele penetrance previously reported ranging from 0.88 to 0.94 (11). All unaffected individuals used in the study were of age above the mean for onset of illness. Disease allele frequency was set to 0.001. Distances and order of genetic markers were set as reported in the CHLC database. Overlapping three point analysis was performed for markers D4S2361, D4S 1647, D4S421, and the PD locus. The 12-allele D4S2380 locus was not included because of prohibitive run time. Multipoint analysis was performed on an IBM SP2 parallel computer and the SGI Challenge machine. Changes have been made in the pedigree shown to protect patient confidentiality.
27. Samples were collected upon informed consent prior to all genetic and clinical tests. The kindred originated in the town of Contursi in the Salerno province of southern Italy (11); some members emigrated to the United States, Germany, and other countries. The extended family pedigree consists of 592 members wiih 60 individuals affected by PD (Fig. 1). High molecular weight genomic DNA was isolated from whole-blood lysate as described [G. I. Bell, J. Karam, W. Rutter, Proc. Natl. Acad. Sci. U.S.A. 78, 5979 (1981)]. Genotyping was performed as described [J. M. Gyapay et al., Nature Genet 7, 262 (1994)]. Pair-wise linkage analysis was performed by means of the MLINK program of the FASTLINK package. [G. M. Lathrop, J. M. Lalouel, C. Julier, J. Ott. Proc. Natl. Acad. Sci. U.S.A. 81, 3442 (1984); R. W. Cottingham, R. M. Idury, A. A. Schaffer, Am. J. Hum. Genet. 54, 252 (1984); S. K. Gupta, A. A. Schaffer, A. L. Cox, S. Dwarkadas, W. Zwaenepoel, Comp. Biomed. Res. 28, 116 (1995).] Allele frequencies were used as reported in the Genome Data Base (http://gdbwww.gdb.org) and the Cooperative Human Linkage Consortium (CHLC) database (http:// www.chlc.org). Multipoint analysis was performed with the LINKMAP program of the FASTLINK package. For the multipoint analysis allele frequencies were set to 1/n where n equals the number of alleles observed. In the two-point analysis, lod scores were calculated for both the reported and the 1/n allele frequencies with minimal effect on the maximum lod score observed. Simulations of multipoint analysis in a subset of the pedigree with different allele frequencies similarly indicated no significant effect on the scores calculated. Maximum lod scores as shown were observed for the heterozygote and homozygote disease allele penetrance set to 0.99 which is similar to the PD allele penetrance previously reported ranging from 0.88 to 0.94 (11). All unaffected individuals used in the study were of age above the mean for onset of illness. Disease allele frequency was set to 0.001. Distances and order of genetic markers were set as reported in the CHLC database. Overlapping three point analysis was performed for markers D4S2361, D4S 1647, D4S421, and the PD locus. The 12-allele D4S2380 locus was not included because of prohibitive run time. Multipoint analysis was performed on an IBM SP2 parallel computer and the SGI Challenge machine. Changes have been made in the pedigree shown to protect patient confidentiality.
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35. Supported in part by the intramural research program for the National Center for Human Genome Research (NCHGR), the National Institute of Neurological Disorders and Stroke (NINDS), the American Parkinson's Disease Association, and the Parkinson Disease Foundation. The authors wish to thank V. Bonavita, P. Vieregge, R. L. Boyer, J. S. Rubenstein, V. V. McKoy, and Y. Chen for their contribution to this study, and Z. Hall for his continuing encouragement and support. This work is dedicated to the memory of Professor G. C. Cotzias for his pioneering work in the treatment of Parkinson's disease.