Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region

Science

Volumn 274, Issue 5292, 1996, Pages 1527-1531

  Lesch, Klaus Peter ^a   Bengel, Dietmar ^b   Heils, Armin ^a   Sabol, Sue Z ^c   Greenberg, Benjamin D ^b   Petri, Susanne ^a   Benjamin, Jonathan ^b   Müller, Clemens R ^a   Hamer, Dean H ^c   Murphy, Dennis L ^b  

^a UNIVERSITY OF WÜRZBURG   (Germany)

^b NATIONAL INSTITUTE OF MENTAL HEALTH   (United States)

^c NATIONAL CANCER INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ADENYLATE CYCLASE; CARRIER PROTEIN; CYCLIC AMP DEPENDENT PROTEIN KINASE; FORSKOLIN; MESSENGER RNA; PHORBOL 13 ACETATE 12 MYRISTATE; PROTEIN KINASE C; SEROTONIN;

AMINE TRANSPORT; ANXIETY NEUROSIS; ARTICLE; GENE FREQUENCY; GENETIC POLYMORPHISM; GENETIC TRANSCRIPTION; GENETIC VARIABILITY; GENOTYPE; HUMAN; HUMAN CELL; INHERITANCE; LYMPHOBLAST; MAJOR CLINICAL STUDY; PERSONALITY; POLYMERASE CHAIN REACTION; PRIORITY JOURNAL; PROMOTER REGION; PROTEIN EXPRESSION; TRANSCRIPTION REGULATION;

ADOLESCENT; ADULT; ALLELES; ANXIETY DISORDERS; CARRIER PROTEINS; CELL LINE; FEMALE; GENETIC MARKERS; GENOTYPE; HUMANS; MALE; MEMBRANE GLYCOPROTEINS; MEMBRANE TRANSPORT PROTEINS; MIDDLE AGED; NERVE TISSUE PROTEINS; NEUROTIC DISORDERS; NUCLEAR FAMILY; PERSONALITY TESTS; PHENOTYPE; POLYMORPHISM, GENETIC; PROMOTER REGIONS (GENETICS); SEROTONIN; SEROTONIN PLASMA MEMBRANE TRANSPORT PROTEINS; TRANSFECTION;

ANIMALIA;

EID: 0006463359     PISSN: 00368075     EISSN: None     Source Type: Journal    
DOI: 10.1126/science.274.5292.1527     Document Type: Article

References (78)

1. J. A. Gray, The Neuropsychology of Anxiety: An Inquiry into the Functions of the Septo-Hippocampal System (Oxford Science, New York, 1982); C. R. Cloninger, Psychiatr. Dev. 4, 167 (1986); H. J. Eysenck, in Handbook of Abnormal Psychology H. J. Eysenck, Ed. (Pitman, London, 1957), pp. 131-156.
2. J. A. Gray, The Neuropsychology of Anxiety: An Inquiry into the Functions of the Septo-Hippocampal System (Oxford Science, New York, 1982); C. R. Cloninger, Psychiatr. Dev. 4, 167 (1986); H. J. Eysenck, in Handbook of Abnormal Psychology H. J. Eysenck, Ed. (Pitman, London, 1957), pp. 131-156.
3. J. A. Gray, The Neuropsychology of Anxiety: An Inquiry into the Functions of the Septo-Hippocampal System (Oxford Science, New York, 1982); C. R. Cloninger, Psychiatr. Dev. 4, 167 (1986); H. J. Eysenck, in Handbook of Abnormal Psychology H. J. Eysenck, Ed. (Pitman, London, 1957), pp. 131-156.
4. C. R. Cloninger, Arch Gen. Psychiatry 44, 573 (1987).
5. _, Psychiatr. Dev. 6, 83 (1988).
6. J. C. Loehlin, Am. Psychol. 44, 1285 (1989); A. C. Heath, C. R. Cloninger, N. G. Martin, J. Pers Soc. Psychol. 66, 762 (1994); R, Plomin, M. J. Owen, P. McGuffin, Science 264, 1733 (1994); C. S. Bergeman et al., Psychol. Aging 3, 399 (1988); N. L. Pedersen et al., J. Pers. Soc. Psychol. 55, 950 (1988); E S. Lander and N. J. Schork, Science 265, 2037 (1994).
7. J. C. Loehlin, Am. Psychol. 44, 1285 (1989); A. C. Heath, C. R. Cloninger, N. G. Martin, J. Pers Soc. Psychol. 66, 762 (1994); R, Plomin, M. J. Owen, P. McGuffin, Science 264, 1733 (1994); C. S. Bergeman et al., Psychol. Aging 3, 399 (1988); N. L. Pedersen et al., J. Pers. Soc. Psychol. 55, 950 (1988); E S. Lander and N. J. Schork, Science 265, 2037 (1994).
8. J. C. Loehlin, Am. Psychol. 44, 1285 (1989); A. C. Heath, C. R. Cloninger, N. G. Martin, J. Pers Soc. Psychol. 66, 762 (1994); R, Plomin, M. J. Owen, P. McGuffin, Science 264, 1733 (1994); C. S. Bergeman et al., Psychol. Aging 3, 399 (1988); N. L. Pedersen et al., J. Pers. Soc. Psychol. 55, 950 (1988); E S. Lander and N. J. Schork, Science 265, 2037 (1994).
9. J. C. Loehlin, Am. Psychol. 44, 1285 (1989); A. C. Heath, C. R. Cloninger, N. G. Martin, J. Pers Soc. Psychol. 66, 762 (1994); R, Plomin, M. J. Owen, P. McGuffin, Science 264, 1733 (1994); C. S. Bergeman et al., Psychol. Aging 3, 399 (1988); N. L. Pedersen et al., J. Pers. Soc. Psychol. 55, 950 (1988); E S. Lander and N. J. Schork, Science 265, 2037 (1994).
10. J. C. Loehlin, Am. Psychol. 44, 1285 (1989); A. C. Heath, C. R. Cloninger, N. G. Martin, J. Pers Soc. Psychol. 66, 762 (1994); R, Plomin, M. J. Owen, P. McGuffin, Science 264, 1733 (1994); C. S. Bergeman et al., Psychol. Aging 3, 399 (1988); N. L. Pedersen et al., J. Pers. Soc. Psychol. 55, 950 (1988); E S. Lander and N. J. Schork, Science 265, 2037 (1994).
11. J. C. Loehlin, Am. Psychol. 44, 1285 (1989); A. C. Heath, C. R. Cloninger, N. G. Martin, J. Pers Soc. Psychol. 66, 762 (1994); R, Plomin, M. J. Owen, P. McGuffin, Science 264, 1733 (1994); C. S. Bergeman et al., Psychol. Aging 3, 399 (1988); N. L. Pedersen et al., J. Pers. Soc. Psychol. 55, 950 (1988); E S. Lander and N. J. Schork, Science 265, 2037 (1994).
12. H. T. Chen, M. Clark, D. Goldman, J. Pharmacol. Toxicol. Methods 27, 209 (1992); J. G. Hensler et al. Synapse 17, 1 (1994); P. Whitaker-Azmitia and S. Peroutka, Ann. N.Y. Acad. Sci. 600, 4 (1990); H. G. Westenberg, D. L. Murphy, J. A. Den Boer, Eds., Advances in the Neurobiology of Anxiety Disorders (Wiley, New York, 1996).
13. H. T. Chen, M. Clark, D. Goldman, J. Pharmacol. Toxicol. Methods 27, 209 (1992); J. G. Hensler et al. Synapse 17, 1 (1994); P. Whitaker-Azmitia and S. Peroutka, Ann. N.Y. Acad. Sci. 600, 4 (1990); H. G. Westenberg, D. L. Murphy, J. A. Den Boer, Eds., Advances in the Neurobiology of Anxiety Disorders (Wiley, New York, 1996).
14. H. T. Chen, M. Clark, D. Goldman, J. Pharmacol. Toxicol. Methods 27, 209 (1992); J. G. Hensler et al. Synapse 17, 1 (1994); P. Whitaker-Azmitia and S. Peroutka, Ann. N.Y. Acad. Sci. 600, 4 (1990); H. G. Westenberg, D. L. Murphy, J. A. Den Boer, Eds., Advances in the Neurobiology of Anxiety Disorders (Wiley, New York, 1996).
15. H. T. Chen, M. Clark, D. Goldman, J. Pharmacol. Toxicol. Methods 27, 209 (1992); J. G. Hensler et al. Synapse 17, 1 (1994); P. Whitaker-Azmitia and S. Peroutka, Ann. N.Y. Acad. Sci. 600, 4 (1990); H. G. Westenberg, D. L. Murphy, J. A. Den Boer, Eds., Advances in the Neurobiology of Anxiety Disorders (Wiley, New York, 1996).
16. K. P. Lesch et al., J. Neural Transm. 91. 67 (1993); K. P. Lesch et al., ibid. 95, 157 (1994).
17. K. P. Lesch et al., J. Neural Transm. 91. 67 (1993); K. P. Lesch et al., ibid. 95, 157 (1994).
18. J. Gelernter, A. J. Pakstis, K. K. Kidd, Hum. Genet. 95, 677 (1995).
19. S. Ramamoorthy et al., Proc. Natl. Acad. Sci. U.S.A. 90, 2542 (1993).
20. K. P. Lesch et al., Bol. Psychiatry 37, 215 (1995); M. Altemus et al., Am. J. Med. Genet. Neuropsychiatr Genet. 67, 409 (1996); D. Di Bella et al., Psychiatr Genet. 5, S100 (1996); A. D. Ogillvie et al., Lancet 347, 731 (1996); D, Collier et al., Neuroreport 7, 1675 (1996).
21. K. P. Lesch et al., Bol. Psychiatry 37, 215 (1995); M. Altemus et al., Am. J. Med. Genet. Neuropsychiatr Genet. 67, 409 (1996); D. Di Bella et al., Psychiatr Genet. 5, S100 (1996); A. D. Ogillvie et al., Lancet 347, 731 (1996); D, Collier et al., Neuroreport 7, 1675 (1996).
22. K. P. Lesch et al., Bol. Psychiatry 37, 215 (1995); M. Altemus et al., Am. J. Med. Genet. Neuropsychiatr Genet. 67, 409 (1996); D. Di Bella et al., Psychiatr Genet. 5, S100 (1996); A. D. Ogillvie et al., Lancet 347, 731 (1996); D, Collier et al., Neuroreport 7, 1675 (1996).
23. K. P. Lesch et al., Bol. Psychiatry 37, 215 (1995); M. Altemus et al., Am. J. Med. Genet. Neuropsychiatr Genet. 67, 409 (1996); D. Di Bella et al., Psychiatr Genet. 5, S100 (1996); A. D. Ogillvie et al., Lancet 347, 731 (1996); D, Collier et al., Neuroreport 7, 1675 (1996).
24. K. P. Lesch et al., Bol. Psychiatry 37, 215 (1995); M. Altemus et al., Am. J. Med. Genet. Neuropsychiatr Genet. 67, 409 (1996); D. Di Bella et al., Psychiatr Genet. 5, S100 (1996); A. D. Ogillvie et al., Lancet 347, 731 (1996); D, Collier et al., Neuroreport 7, 1675 (1996).
25. A. Heils et al., J. Neural Transm. 102, 247 (1995); A. Heils et al., J. Neurochem. 66, 2621 (1996).
26. A. Heils et al., J. Neural Transm. 102, 247 (1995); A. Heils et al., J. Neurochem. 66, 2621 (1996).
27. 2. and 1 U of Taq DNA polymerase. Annealing was carried out at 61°C for 30 s, extension at 72°C for 1 min, and denaturation at 95°C for 30 s for 35 cycles.
28. K. Iken et al., Cell, Immunol. 163, 1 (1995); B. A. Faraj, Z. L. Olkowski, R. T. Jackson, Int. J. Immunopharmacol. 16, 561 (1994).
29. K. Iken et al., Cell, Immunol. 163, 1 (1995); B. A. Faraj, Z. L. Olkowski, R. T. Jackson, Int. J. Immunopharmacol. 16, 561 (1994).
30. 2. For induction of 5-HTT expression, lymphoblasts were treated with 50 to 200 μM forskolin or 0.5 to 2 μM PMA and grown for an additional 24 hours.
31. 5 cells) were exposed for 24 hours to 5 μg of construct DNA complexed with 5 μl of Transfectam lipofectin reagent (Promega) in 5 ml of RPMI 1640. Cells were grown for an additional 24 hours before harvest in 1 ml of luciferase lysis buffer. Extracts were assayed for luciferase activity by addition of 10 μl of cell lysate samples at 15-s intervals to 100 ml of luciferin reagent. Chemiluminescence was counted for 15 s at a constant time (90 s) after reagent mixing in a liquid scintillation spectrometer.
32. Total RNA was isolated from lymphoblasts (13) by guanidine thiocyanate column purification (Qiagen). The 28S/18S bands of ribosomal RNA were analyzed by densitometry to control for variations in RNA concentration, and single-stranded cDNA (37°C, 60 min) was synthesized with random primer. 5-HTT mRNA was measured by semiquantitative competitive reverse transcription PCR with a 5-HT T cDNA-derived template containing a 172-bp deletion (base pairs 1635 to 1806) as internal standard. The PCR amplification (30 s at 95°C, 30 s at 61°C, 1 min at 72°C for 35 cycles) of 355- or 527-bp fragments was carried out with the amplimers se3 (5′-ATGCA-GAAGCGATAGCCAACATG, base pairs 1437 to 1459 with respect to the transcription initiation site) and 3re (5′-AGATGAGGTTCCTATGCAGTAAC, base pairs 2147 to 2167), 5-HTT mRNA concentrations of lymphoblast cell lines with the I/I genotype were first titrated against incremental concentrations of competitive template ranging from 0.01 to 1.0 ng. The concentration of the competitive template at target/template equilibrium was then used to compare mRNA concentrations semiquantitatively in lymphoblast cell lines with different genotypes (13) before and after induction of 5-HTT gene transcription. To control for differences in the efficiency of reverse transcription of mRNA, we performed cDNA synthesis and subsequent competitive PCR in quadruplicate. The reaction products were electrophoresed through 2% agarose, visualized by ultraviolet illumination in the presence of ethidium bromide, and quantified by densitometric analysis.
33. 3H]5-HT for 30 min at 25°C in the absence or presence of 0.1 mM imipramine.
34. J. Benjamin et al., Nature Genet. 12, 81 (1996).
35. Two independent groups of predominantly male siblings, other family members, and unrelated individuals were studied: (i) The NIMH sample (17) was recruited from the NIH and local college campuses by advertising for pairs of brothers and pairs of sisters for a study of personality traits and chromosomes. The sample consisted of 221 subjects, of whom 93% were male and 7% were female. The average age was 23.3 ± 6.8 years (range 18 to 64 years), the average educational level was 15,6 ± 2.1 years (range 12 to 20 years), and the average Kinsey score was 0.2 ± 0.7 (range 0 to 5.6, where 0 is exclusively heterosexual and 6 is exclusively homosexual). The ethnic composition was 79.1% white non-Hispanic, 10.0% Asian/Pacific Islander, 4.1% Hispanic/Latino, 4.1% African American/Black, and 2.7% other. The family structure of the NIMH sample was 208 siblings from 104 families and 13 unrelated individuals. (ii) The NCI sample [D. H. Hamer et al., Science 261, 321 (1993); S. Hu et al., Nature Genet. 11, 248 (1995)] was collected from NIH clinics and local and national homophile organizations for a study of sexual orientation, HIV progression, and psychological traits. The sample consisted of 284 subjects of whom 92% were male and 8% were female. The average age was 37.6 ± 9.7 years (range 18 to 72 years), the average educational level was 17.3 ± 2.6 years (range 12 to 20 years), and the average Kinsey score was 4.8 ± 2.0 (range 0 to 6). The ethnic composition was 93.6% white non-Hispanic, 5.3% Hispanic/Latino, 0.7% African American/Black, 0.4% Native American/Alaskan, and 0.4% other. The family structure of the NCI sample was 251 siblings from 106 families, 9 parents, and 24 unrelated individuals.
36. Two independent groups of predominantly male siblings, other family members, and unrelated individuals were studied: (i) The NIMH sample (17) was recruited from the NIH and local college campuses by advertising for pairs of brothers and pairs of sisters for a study of personality traits and chromosomes. The sample consisted of 221 subjects, of whom 93% were male and 7% were female. The average age was 23.3 ± 6.8 years (range 18 to 64 years), the average educational level was 15,6 ± 2.1 years (range 12 to 20 years), and the average Kinsey score was 0.2 ± 0.7 (range 0 to 5.6, where 0 is exclusively heterosexual and 6 is exclusively homosexual). The ethnic composition was 79.1% white non-Hispanic, 10.0% Asian/Pacific Islander, 4.1% Hispanic/Latino, 4.1% African American/Black, and 2.7% other. The family structure of the NIMH sample was 208 siblings from 104 families and 13 unrelated individuals. (ii) The NCI sample [D. H. Hamer et al., Science 261, 321 (1993); S. Hu et al., Nature Genet. 11, 248 (1995)] was collected from NIH clinics and local and national homophile organizations for a study of sexual orientation, HIV progression, and psychological traits. The sample consisted of 284 subjects of whom 92% were male and 8% were female. The average age was 37.6 ± 9.7 years (range 18 to 72 years), the average educational level was 17.3 ± 2.6 years (range 12 to 20 years), and the average Kinsey score was 4.8 ± 2.0 (range 0 to 6). The ethnic composition was 93.6% white non-Hispanic, 5.3% Hispanic/Latino, 0.7% African American/Black, 0.4% Native American/Alaskan, and 0.4% other. The family structure of the NCI sample was 251 siblings from 106 families, 9 parents, and 24 unrelated individuals.
37. R. R. McCrae and P. T. J. Costa, Personality in Adulthood (Guilford, New York, 1990).
38. P. T. J. Costa and R. R. McCrae, in Handbook of Personality Inventories, J. Cheek and E. M. Donahue, Eds. (Plenum, New York, in press).
39. G. R. Heninger, Psychopharmacology: The Fourth Generation of Progress. F. E. Bloom and D. J. Kupfer, Eds. (Raven, New York, 1995), p. 471; D. L Murphy et al., in Serotonin: From Cell Biology to Pharmacology and Therapeutics II (Kluwer Academ-ic, Dordrecht, Netherlands, 1993), pp. 223-230; O. Benkert, H. Wetzel, A. Szegedi, Int. Clin. Psychopharmacol. 8 (suppl. 1), 3 (1993).
40. G. R. Heninger, Psychopharmacology: The Fourth Generation of Progress. F. E. Bloom and D. J. Kupfer, Eds. (Raven, New York, 1995), p. 471; D. L Murphy et al., in Serotonin: From Cell Biology to Pharmacology and Therapeutics II (Kluwer Academ-ic, Dordrecht, Netherlands, 1993), pp. 223-230; O. Benkert, H. Wetzel, A. Szegedi, Int. Clin. Psychopharmacol. 8 (suppl. 1), 3 (1993).
41. G. R. Heninger, Psychopharmacology: The Fourth Generation of Progress. F. E. Bloom and D. J. Kupfer, Eds. (Raven, New York, 1995), p. 471; D. L Murphy et al., in Serotonin: From Cell Biology to Pharmacology and Therapeutics II (Kluwer Academ-ic, Dordrecht, Netherlands, 1993), pp. 223-230; O. Benkert, H. Wetzel, A. Szegedi, Int. Clin. Psychopharmacol. 8 (suppl. 1), 3 (1993).
42. G. Griebel, Pharmacol. Ther. 65, 319 (1995).
43. S. L. Handley, ibid. 66, 103 (1995).
44. A complete table of the S - L differences and F values for all of the NEO Neuroticism facets, 16PF second-order and primary factors, estimated TPQ factors, and TPQ Harm Avoidance subscales is available from the authors by request.
45. R. B. Cattell, J. Abnorm. Soc. Psychol. 38, 476 (1943); R. B. Cattell, The Description and Measurement of Personality (World Book, Yonkers, NY, 1946); J. S. Wiggins and A. L. Pincus, Annu. Rev. Psychol. 48, 473 (1992).
46. R. B. Cattell, J. Abnorm. Soc. Psychol. 38, 476 (1943); R. B. Cattell, The Description and Measurement of Personality (World Book, Yonkers, NY, 1946); J. S. Wiggins and A. L. Pincus, Annu. Rev. Psychol. 48, 473 (1992).
47. R. B. Cattell, J. Abnorm. Soc. Psychol. 38, 476 (1943); R. B. Cattell, The Description and Measurement of Personality (World Book, Yonkers, NY, 1946); J. S. Wiggins and A. L. Pincus, Annu. Rev. Psychol. 48, 473 (1992).
48. Population association was assessed by one-way analysis of variance (ANOVA) using SPSS Statistical Software.
49. V. T. George and R. C. Elston, Genet. Epidemiol. 4, 193 (1987). Across-pedigrees association was assessed using the ASSOC program of the S.A.G.E. package [R. C. Elston, V. T. George, A. J. M. Sorant, in S.A.G.E. Users Guide, Release 2.2 (Department of Biometry and Genetics, Louisiana State University Medical Center, New Orleans, 1994); T. G. Nick et al., Genet. Epidemiol. 12, 145 (1995)]. Within-pedigrees association was determined by a paired t test using genetically discordant sib-pairs and was conservatively corrected for the nonindependence of siblings from the same family (17).
50. V. T. George and R. C. Elston, Genet. Epidemiol. 4, 193 (1987). Across-pedigrees association was assessed using the ASSOC program of the S.A.G.E. package [R. C. Elston, V. T. George, A. J. M. Sorant, in S.A.G.E. Users Guide, Release 2.2 (Department of Biometry and Genetics, Louisiana State University Medical Center, New Orleans, 1994); T. G. Nick et al., Genet. Epidemiol. 12, 145 (1995)]. Within-pedigrees association was determined by a paired t test using genetically discordant sib-pairs and was conservatively corrected for the nonindependence of siblings from the same family (17).
51. V. T. George and R. C. Elston, Genet. Epidemiol. 4, 193 (1987). Across-pedigrees association was assessed using the ASSOC program of the S.A.G.E. package [R. C. Elston, V. T. George, A. J. M. Sorant, in S.A.G.E. Users Guide, Release 2.2 (Department of Biometry and Genetics, Louisiana State University Medical Center, New Orleans, 1994); T. G. Nick et al., Genet. Epidemiol. 12, 145 (1995)]. Within-pedigrees association was determined by a paired t test using genetically discordant sib-pairs and was conservatively corrected for the nonindependence of siblings from the same family (17).
52. J. A. Den Boer et al., Int. Clin. Psychopharmacol. 9 (suppl. 4), 47 (1995).
53. M. J. Owens and C. B. Nemeroff, Clin. Chem. 40, 288 (1994); L. J. Iny et al., Biol. Psychiatry 36, 281 (1994); G. Faludi, K. Tekes, L. Tothfalusi, J. Psychiatry Neurosci. 19, 109 (1994).
54. M. J. Owens and C. B. Nemeroff, Clin. Chem. 40, 288 (1994); L. J. Iny et al., Biol. Psychiatry 36, 281 (1994); G. Faludi, K. Tekes, L. Tothfalusi, J. Psychiatry Neurosci. 19, 109 (1994).
55. M. J. Owens and C. B. Nemeroff, Clin. Chem. 40, 288 (1994); L. J. Iny et al., Biol. Psychiatry 36, 281 (1994); G. Faludi, K. Tekes, L. Tothfalusi, J. Psychiatry Neurosci. 19, 109 (1994).
56. K. Fuxe et al., Neuropharmacology 22, 389 (1983); C. M. Beasley, D. N. Masica, J. H. Potvin, Psychopharmacology 107, 1 (1992); P. Blier and C. de Montigny, Trends Pharmacol. Sci. 15, 220 (1994); E. H. Cook Jr. et al., Neuropharmacol. Neurotoxicol. 5, 1745 (1994); J. Mai and E. Moryl. J. Neural Transm. 88, 143 (1992).
57. K. Fuxe et al., Neuropharmacology 22, 389 (1983); C. M. Beasley, D. N. Masica, J. H. Potvin, Psychopharmacology 107, 1 (1992); P. Blier and C. de Montigny, Trends Pharmacol. Sci. 15, 220 (1994); E. H. Cook Jr. et al., Neuropharmacol. Neurotoxicol. 5, 1745 (1994); J. Mai and E. Moryl. J. Neural Transm. 88, 143 (1992).
58. K. Fuxe et al., Neuropharmacology 22, 389 (1983); C. M. Beasley, D. N. Masica, J. H. Potvin, Psychopharmacology 107, 1 (1992); P. Blier and C. de Montigny, Trends Pharmacol. Sci. 15, 220 (1994); E. H. Cook Jr. et al., Neuropharmacol. Neurotoxicol. 5, 1745 (1994); J. Mai and E. Moryl. J. Neural Transm. 88, 143 (1992).
59. K. Fuxe et al., Neuropharmacology 22, 389 (1983); C. M. Beasley, D. N. Masica, J. H. Potvin, Psychopharmacology 107, 1 (1992); P. Blier and C. de Montigny, Trends Pharmacol. Sci. 15, 220 (1994); E. H. Cook Jr. et al., Neuropharmacol. Neurotoxicol. 5, 1745 (1994); J. Mai and E. Moryl. J. Neural Transm. 88, 143 (1992).
60. K. Fuxe et al., Neuropharmacology 22, 389 (1983); C. M. Beasley, D. N. Masica, J. H. Potvin, Psychopharmacology 107, 1 (1992); P. Blier and C. de Montigny, Trends Pharmacol. Sci. 15, 220 (1994); E. H. Cook Jr. et al., Neuropharmacol. Neurotoxicol. 5, 1745 (1994); J. Mai and E. Moryl. J. Neural Transm. 88, 143 (1992).
61. D. L. Shuey, T. W. Sadler, J. M. Lauder, Teratology 46, 367 (1992).
62. A. H. Paterson et al., Genetics 127, 181 (1991); C. W. Stuber et al., ibid. 132, 823 (1992); J. Flint et al., Science 269, 1432 (1995); R. P. Ebstein et al., Nature Genet. 12, 78 (1996); T. Ohno, S. Kawazu, S. Tomono, Metabolism 45 218 (1996); F. Cambien et al., Nature 359, 641 (1992); E. Arbustini et al., Br. Heart J. 74, 584 (1995); F. Gambien, Clin. Genet. 46, 94 (1994); A. Gardemann et al., Circulation 92, 2796 (1995).
63. A. H. Paterson et al., Genetics 127, 181 (1991); C. W. Stuber et al., ibid. 132, 823 (1992); J. Flint et al., Science 269, 1432 (1995); R. P. Ebstein et al., Nature Genet. 12, 78 (1996); T. Ohno, S. Kawazu, S. Tomono, Metabolism 45 218 (1996); F. Cambien et al., Nature 359, 641 (1992); E. Arbustini et al., Br. Heart J. 74, 584 (1995); F. Gambien, Clin. Genet. 46, 94 (1994); A. Gardemann et al., Circulation 92, 2796 (1995).
64. A. H. Paterson et al., Genetics 127, 181 (1991); C. W. Stuber et al., ibid. 132, 823 (1992); J. Flint et al., Science 269, 1432 (1995); R. P. Ebstein et al., Nature Genet. 12, 78 (1996); T. Ohno, S. Kawazu, S. Tomono, Metabolism 45 218 (1996); F. Cambien et al., Nature 359, 641 (1992); E. Arbustini et al., Br. Heart J. 74, 584 (1995); F. Gambien, Clin. Genet. 46, 94 (1994); A. Gardemann et al., Circulation 92, 2796 (1995).
65. A. H. Paterson et al., Genetics 127, 181 (1991); C. W. Stuber et al., ibid. 132, 823 (1992); J. Flint et al., Science 269, 1432 (1995); R. P. Ebstein et al., Nature Genet. 12, 78 (1996); T. Ohno, S. Kawazu, S. Tomono, Metabolism 45 218 (1996); F. Cambien et al., Nature 359, 641 (1992); E. Arbustini et al., Br. Heart J. 74, 584 (1995); F. Gambien, Clin. Genet. 46, 94 (1994); A. Gardemann et al., Circulation 92, 2796 (1995).
66. A. H. Paterson et al., Genetics 127, 181 (1991); C. W. Stuber et al., ibid. 132, 823 (1992); J. Flint et al., Science 269, 1432 (1995); R. P. Ebstein et al., Nature Genet. 12, 78 (1996); T. Ohno, S. Kawazu, S. Tomono, Metabolism 45 218 (1996); F. Cambien et al., Nature 359, 641 (1992); E. Arbustini et al., Br. Heart J. 74, 584 (1995); F. Gambien, Clin. Genet. 46, 94 (1994); A. Gardemann et al., Circulation 92, 2796 (1995).
67. A. H. Paterson et al., Genetics 127, 181 (1991); C. W. Stuber et al., ibid. 132, 823 (1992); J. Flint et al., Science 269, 1432 (1995); R. P. Ebstein et al., Nature Genet. 12, 78 (1996); T. Ohno, S. Kawazu, S. Tomono, Metabolism 45 218 (1996); F. Cambien et al., Nature 359, 641 (1992); E. Arbustini et al., Br. Heart J. 74, 584 (1995); F. Gambien, Clin. Genet. 46, 94 (1994); A. Gardemann et al., Circulation 92, 2796 (1995).
68. A. H. Paterson et al., Genetics 127, 181 (1991); C. W. Stuber et al., ibid. 132, 823 (1992); J. Flint et al., Science 269, 1432 (1995); R. P. Ebstein et al., Nature Genet. 12, 78 (1996); T. Ohno, S. Kawazu, S. Tomono, Metabolism 45 218 (1996); F. Cambien et al., Nature 359, 641 (1992); E. Arbustini et al., Br. Heart J. 74, 584 (1995); F. Gambien, Clin. Genet. 46, 94 (1994); A. Gardemann et al., Circulation 92, 2796 (1995).
69. A. H. Paterson et al., Genetics 127, 181 (1991); C. W. Stuber et al., ibid. 132, 823 (1992); J. Flint et al., Science 269, 1432 (1995); R. P. Ebstein et al., Nature Genet. 12, 78 (1996); T. Ohno, S. Kawazu, S. Tomono, Metabolism 45 218 (1996); F. Cambien et al., Nature 359, 641 (1992); E. Arbustini et al., Br. Heart J. 74, 584 (1995); F. Gambien, Clin. Genet. 46, 94 (1994); A. Gardemann et al., Circulation 92, 2796 (1995).
70. A. H. Paterson et al., Genetics 127, 181 (1991); C. W. Stuber et al., ibid. 132, 823 (1992); J. Flint et al., Science 269, 1432 (1995); R. P. Ebstein et al., Nature Genet. 12, 78 (1996); T. Ohno, S. Kawazu, S. Tomono, Metabolism 45 218 (1996); F. Cambien et al., Nature 359, 641 (1992); E. Arbustini et al., Br. Heart J. 74, 584 (1995); F. Gambien, Clin. Genet. 46, 94 (1994); A. Gardemann et al., Circulation 92, 2796 (1995).
71. R. T. Mulder, P. R. Joyce, C. R. Cloninger, Compr. Psychiatry 35, 225 (1994); D. M. Svrakic et al., Arch. Gen. Psychiatry 50, 991 (1993); G. Andrews et al., J. Affective Disord 19, 23 (1990); K. S. Kendler et al., Arch. Gen. Psychiatry 50, 863 (1993); A. MacKinnon and P. M. Mitchell, in Handbook of Depression and Anxiety, J. Den Boer and J. M. Ad Sitsen, Eds. (Dekker, New York, 1994), pp. 71-119; K. S. Kendler et al., Arch. Gen. Psychiatry 44, 451 (1987); D. Collier et al., Mol. Psychiatry, in press.
72. R. T. Mulder, P. R. Joyce, C. R. Cloninger, Compr. Psychiatry 35, 225 (1994); D. M. Svrakic et al., Arch. Gen. Psychiatry 50, 991 (1993); G. Andrews et al., J. Affective Disord 19, 23 (1990); K. S. Kendler et al., Arch. Gen. Psychiatry 50, 863 (1993); A. MacKinnon and P. M. Mitchell, in Handbook of Depression and Anxiety, J. Den Boer and J. M. Ad Sitsen, Eds. (Dekker, New York, 1994), pp. 71-119; K. S. Kendler et al., Arch. Gen. Psychiatry 44, 451 (1987); D. Collier et al., Mol. Psychiatry, in press.
73. R. T. Mulder, P. R. Joyce, C. R. Cloninger, Compr. Psychiatry 35, 225 (1994); D. M. Svrakic et al., Arch. Gen. Psychiatry 50, 991 (1993); G. Andrews et al., J. Affective Disord 19, 23 (1990); K. S. Kendler et al., Arch. Gen. Psychiatry 50, 863 (1993); A. MacKinnon and P. M. Mitchell, in Handbook of Depression and Anxiety, J. Den Boer and J. M. Ad Sitsen, Eds. (Dekker, New York, 1994), pp. 71-119; K. S. Kendler et al., Arch. Gen. Psychiatry 44, 451 (1987); D. Collier et al., Mol. Psychiatry, in press.
74. R. T. Mulder, P. R. Joyce, C. R. Cloninger, Compr. Psychiatry 35, 225 (1994); D. M. Svrakic et al., Arch. Gen. Psychiatry 50, 991 (1993); G. Andrews et al., J. Affective Disord 19, 23 (1990); K. S. Kendler et al., Arch. Gen. Psychiatry 50, 863 (1993); A. MacKinnon and P. M. Mitchell, in Handbook of Depression and Anxiety, J. Den Boer and J. M. Ad Sitsen, Eds. (Dekker, New York, 1994), pp. 71-119; K. S. Kendler et al., Arch. Gen. Psychiatry 44, 451 (1987); D. Collier et al., Mol. Psychiatry, in press.
75. R. T. Mulder, P. R. Joyce, C. R. Cloninger, Compr. Psychiatry 35, 225 (1994); D. M. Svrakic et al., Arch. Gen. Psychiatry 50, 991 (1993); G. Andrews et al., J. Affective Disord 19, 23 (1990); K. S. Kendler et al., Arch. Gen. Psychiatry 50, 863 (1993); A. MacKinnon and P. M. Mitchell, in Handbook of Depression and Anxiety, J. Den Boer and J. M. Ad Sitsen, Eds. (Dekker, New York, 1994), pp. 71-119; K. S. Kendler et al., Arch. Gen. Psychiatry 44, 451 (1987); D. Collier et al., Mol. Psychiatry, in press.
76. R. T. Mulder, P. R. Joyce, C. R. Cloninger, Compr. Psychiatry 35, 225 (1994); D. M. Svrakic et al., Arch. Gen. Psychiatry 50, 991 (1993); G. Andrews et al., J. Affective Disord 19, 23 (1990); K. S. Kendler et al., Arch. Gen. Psychiatry 50, 863 (1993); A. MacKinnon and P. M. Mitchell, in Handbook of Depression and Anxiety, J. Den Boer and J. M. Ad Sitsen, Eds. (Dekker, New York, 1994), pp. 71-119; K. S. Kendler et al., Arch. Gen. Psychiatry 44, 451 (1987); D. Collier et al., Mol. Psychiatry, in press.
77. R. T. Mulder, P. R. Joyce, C. R. Cloninger, Compr. Psychiatry 35, 225 (1994); D. M. Svrakic et al., Arch. Gen. Psychiatry 50, 991 (1993); G. Andrews et al., J. Affective Disord 19, 23 (1990); K. S. Kendler et al., Arch. Gen. Psychiatry 50, 863 (1993); A. MacKinnon and P. M. Mitchell, in Handbook of Depression and Anxiety, J. Den Boer and J. M. Ad Sitsen, Eds. (Dekker, New York, 1994), pp. 71-119; K. S. Kendler et al., Arch. Gen. Psychiatry 44, 451 (1987); D. Collier et al., Mol. Psychiatry, in press.
78. We thank M. Schad, G. Ortega, and S. Jatzke for technical assistance, W. Davis and D. Drake for editorial assistance, and M. Atemus, J. Mizrahi, and A. Jaffe for logistical support. Supported by the Deutsche Forschungsgemeinschaft, the Bundesministerium für Bildung und Forschung, the European Commission, and the Intramural Research Programs of NIMH and NCI, K.P.L. is supported by the Hermann and Lilly Schilling Foundation.