An association between schizophrenic disorders and phenylketonuria (PKU) and heterozygosity for PKU has long been suggested. Since the discovery of PKU in 1934, schizophrenia and other psychotic illnesses have been frequently reported in affected individuals and in their relatives. More recently, schizotypal behavior and other abnormal behaviors have been reported in treated phenylketonurics. To test the hypothesis that PKU heterozygosity is a risk factor for schizophrenia, a study is proposed in which the proportion of PKU heterozygotes in a group of 300 schizophrenic patients will be compared with a group of 600 unaffected individuals (about 2% of normal individuals should be heterozygotes). A study of this size should allow detection of a three-fold increase in the heterozygosity rate among those with schizophrenia. Schizophrenic cases will be so designated based on the administration of a structured clinical interview and on an extensive review of medical and psychiatric records from a variety of sources. All definite cases and all normal subjects will be asked to donate approximately 15 milliliters of blood and to complete a brief questionnaire regarding ethnic background, socioeconomic status, family history of mental illness, the name of a family member for future contact, and other pedigree data (cases only). With DNA extracted from this blood, an accurate determination of PKU heterozygosity status will be made through the use of oligonucleotide probes for normal and mutant alleles of the phenylalanine hydroxylase gene. This is now possible because of the recent discovery that only four or five mutations account for over 90% of PKU alleles. Two of the causative mutations have been elucidated, and data on the remaining mutations should be available within the next several months. While the above hypothesis is the major focus of this proposal, the availability o DNA from a large numb-er of patients and normal subjects will greatly facilitate the testing, through the use of molecular genetic techniques, of other genes that possibly predispose to schizophrenia. In addition, if a family-based linkage study delineates predisposing polymorphism or mutation, the generality of the finding can be rapidly estimated by analyzing our sample of schizophrenics. Finally, pedigree data collected from the cases can be used to identify large families with multiple affected members; such families will be useful for the future generation of a family-based DNA bank which would complement the,cross-sectional bank generated by this project

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH044276-03
Application #
3383792
Study Section
Psychopathology and Clinical Biology Research Review Committee (PCB)
Project Start
1989-09-30
Project End
1992-08-31
Budget Start
1991-09-01
Budget End
1992-08-31
Support Year
3
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
City
Rochester
State
MN
Country
United States
Zip Code
55905
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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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