Linkage analysis can be problematic when applied to the multifactorial disease of schizophrenia. Obstacles to the success of linkage analysis include genetic heterogeneity, reduced penetrance, paucity of large multiplex families, difficulty in disease diagnosis in relatives, the possibility of phenocopies, and the possibility that misspecification of the genetic model may strongly affect the results of multipoint linkage. RFLP-based case-control association studies also may be problematic because they rely both on linkage between the RFLP and the causative mutation(s) as well as on linkage disequilibrium between the RFLP marker and the causative mutation(s). With the advent of the polymerase chain reaction (PCR) and adjunct methodology, another approach to elucidating the genetic predisposition to schizophrenia has become possible. The approach is two-tiered and first involves the identification in candidate genes of DNA sequence variations that produce structural alterations in the protein or affect the consensus segments that regulate the level of gene expression. Many of these variations will be of functional significance. Such sequence variations can be detected by direct genomic sequencing or by screening with other PCR-based methodologies such as single strand conformation polymorphism analysis in a sample of schizophrenics. Once a sequence variation of likely functional significance is found in a candidate gene, the prevalence of that allele is compared in a large group of unrelated schizophrenic cases and ethnically-similar controls to determine if a disease association exists. We have established a DNA bank on nearly 500 DSM-III-R defined schizophrenics and 1200 controls and have tested two candidate genes for an association with schizophrenia. Herein, we propose to: 1) expand the study sample to 900 cases and 1800 controls; 2) partially test the dopamine and norepinephrine hypotheses of schizophrenia by searching for sequence variants of likely functional significance in at least 15 candidate genes in the """"""""catecholamine system"""""""" and testing any such variants for disease associations in the case-control sample; and, 3) develop methodology for rapidly and accurately detecting single basepair changes in candidate genes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH044276-07
Application #
2246056
Study Section
Psychopathology and Clinical Biology Research Review Committee (PCB)
Project Start
1989-09-30
Project End
1996-08-31
Budget Start
1995-09-01
Budget End
1996-08-31
Support Year
7
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
City
Rochester
State
MN
Country
United States
Zip Code
55905
Feng, J; Sobell, J L; Heston, L L et al. (1998) Scanning of the dopamine D1 and D5 receptor genes by REF in neuropsychiatric patients reveals a novel missense change at a highly conserved amino acid. Am J Med Genet 81:172-8
Feng, J; Sobell, J L; Heston, L L et al. (1998) Variants in the alpha2A AR adrenergic receptor gene in psychiatric patients. Am J Med Genet 81:405-10
Sobell, J L; Lind, T J; Hebrink, D D et al. (1997) Screening the monoamine oxidase B gene in 100 male patients with schizophrenia: a cluster of polymorphisms in African-Americans but lack of functionally significant sequence changes. Am J Med Genet 74:44-9
Liu, Q; Thorland, E C; Sommer, S S (1997) Inhibition of PCR amplification by a point mutation downstream of a primer. Biotechniques 22:292-4, 296, 298, passim
Sobell, J L; Sigurdson, D C; Heston, L L et al. (1996) Genotype-to-phenotype analysis: search for clinical characteristics of a missense change in the GABAA-beta 1 receptor gene. Am J Med Genet 67:81-4
Liu, Q; Feng, J; Sommer, S S (1996) Bi-directional dideoxy fingerprinting (Bi-ddF): a rapid method for quantitative detection of mutations in genomic regions of 300-600 bp. Hum Mol Genet 5:107-14
Liu, Q; Sobell, J L; Heston, L L et al. (1995) Screening the dopamine D1 receptor gene in 131 schizophrenics and eight alcoholics: identification of polymorphisms but lack of functionally significant sequence changes. Am J Med Genet 60:165-71
Sobell, J L; Lind, T J; Sigurdson, D C et al. (1995) The D5 dopamine receptor gene in schizophrenia: identification of a nonsense change and multiple missense changes but lack of association with disease. Hum Mol Genet 4:507-14
Liu, Q; Sommer, S S (1995) Restriction endonuclease fingerprinting (REF): a sensitive method for screening mutations in long, contiguous segments of DNA. Biotechniques 18:470-7
Dutton, C M; Paynton, C; Sommer, S S (1993) General method for amplifying regions of very high G+C content. Nucleic Acids Res 21:2953-4

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