Intermediate phenotypes and genetic mechanisms of psychiatric disorders

Nature Reviews Neuroscience

Volumn 7, Issue 10, 2006, Pages 818-827

  Meyer Lindenberg, Andreas ^a   Weinberger, Daniel R ^a  

^a NATIONAL INSTITUTE OF MENTAL HEALTH   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BRAIN FUNCTION; COGNITION; EMOTION; GENETIC LINKAGE; GENETIC SUSCEPTIBILITY; GENETIC VARIABILITY; GENETICS; HUMAN; MENTAL DISEASE; MOLECULAR IMAGING; MORPHOLOGY; NERVOUS SYSTEM; PHENOTYPE; PRIORITY JOURNAL; REVIEW;

ANIMALS; DIAGNOSTIC IMAGING; GENETIC PREDISPOSITION TO DISEASE; GENOTYPE; HUMANS; MENTAL DISORDERS; MODELS, GENETIC; PHENOTYPE; VARIATION (GENETICS);

EID: 33748924655     PISSN: 1471003X     EISSN: 14710048     Source Type: Journal    
DOI: 10.1038/nrn1993     Document Type: Review

References (95)

1. Sullivan, P. F., Kendler, K. S. & Neale, M. C. Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch. Gen. Psychiatry 60, 1187-1192 (2003).
2. Sullivan, P. F., Neale, M. C. & Kendler, K. S. Genetic epidemiology of major depression: review and metaanalysis. Am. J. Psychiatry 157, 1552-1562 (2000).
3. Weinberger, D. R. et al. Prefrontal neurons and the genetics of schizophrenia. Biol. Psychiatry 50, 825-844 (2001).
4. Meyer-Lindenberg, A. et al. Midbrain dopamine and prefrontal function in humans: interaction and modulation by COMT genotype. Nature Neurosci. 8, 594-596 (2005).
5. Meyer-Lindenberg, A. et al. Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia. Nature Neurosci. 5, 267-271 (2002).
6. Pezawas, L. et al. 5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: a genetic susceptibility mechanism for depression. Nature Neurosci. 8, 828-834 (2005).
7. Waldman, I. D. Statistical approaches to complex phenotypes: evaluating neuropsychological endophenotypes for attention-deficit/hyperactivity disorder. Biol. Psychiatry 57, 1347-1356 (2005).
8. Goldman, D., Oroszi, G. & Ducci, F. The genetics of addictions: uncovering the genes. Nature Rev. Genet. 6, 521-532 (2005).
9. Belmonte, M. K. et al. Autism as a disorder of neural information processing: directions for research and targets for therapy. Mol. Psychiatry 9, 646-663 (2004).
10. Riley, B. P. & McGuffin, P. Linkage and associated studies of schizophrenia. Am. J. Med. Genet. 97, 23-44 (2000).
11. Menzel, S. Genetic and molecular analyses of complex metabolic disorders: genetic linkage. Ann. NY Acad. Sci. 967, 249-257 (2002).
12. Harrison, P. J. & Weinberger, D. R. Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol. Psychiatry 10, 40-68 (2005).
13. Risch, N. Genetic linkage and complex diseases, with special reference to psychiatric disorders. Genet. Epidemiol. 7, 3-16; discussion 17-45 (1990).
14. Gottesman, I. I. & Shields, J. A polygenic theory of schizophrenia. Proc. Natl Acad. Sci. USA 58, 199-205 (1967).
15. Page, G. P., George, V., Go, R. C., Page, P. Z. & Allison, D. B. 'Are we there yet?': Deciding when one has demonstrated specific genetic causation in complex diseases and quantitative traits. Am. J. Hum. Genet. 73, 711-719 (2003).
16. Deschepper, C. F., Boutin-Ganache, I., Zahabi, A. & Jiang, Z. In search of cardiovascular candidate genes: interactions between phenotypes and genotypes. Hypertension 39, 332-336 (2002).
17. Gottesman, I. I. & Gould, T. D. The endophenotype concept in psychiatry: etymology and strategic intentions. Am. J. Psychiatry 160, 636-645 (2003).
18. Almasy, L. & Blangero, J. Endophenotypes as quantitative risk factors for psychiatric disease: rationale and study design. Am. J. Med. Genet. 105, 42-44 (2001).
19. Weinberger, D. R. Schizophrenia: new phenes and new genes. Biol. Psychiatry 46, 3-7 (1999).
20. Alexander, G. E., DeLong, M. R. & Strick, P. L. Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu. Rev. Neurosci. 9, 357-381 (1986).
21. Goldman-Rakic, P. S., Selemon, L. D. & Schwartz, M. L. Dual pathways connecting the dorsolateral prefrontal cortex with the hippocampal formation and parahippocampal cortex in the rhesus monkey. Neuroscience 12, 719-743 (1984).
22. Friston, K. J. The disconnection hypothesis. Schizophr. Res. 30, 115-125 (1998).
23. Meyer-Lindenberg, A. S. et al. Regionally specific disturbance of dorsolateral prefrontal-hippocampal functional connectivity in schizophrenia. Arch. Gen. Psychiatry 62, 379-386 (2005).
24. Dunnett, S. B., Meldrum, A. & Muir, J. L. Frontal-striatal disconnection disrupts cognitive performance of the frontal-type in the rat. Neuroscience 135, 1055-1065 (2005).
25. Pantelis, C. et al. Frontal-striatal cognitive deficits in patients with chronic schizophrenia. Brain 120, 1823-1843 (1997).
26. Swerdlow, N. R., Geyer, M. A. & Braff, D. L. Neural circuit regulation of prepulse inhibition of startle in the rat: current knowledge and future challenges. Psychopharmacology (Berl.) 156, 194-215 (2001).
27. Carlsson, A. A paradigm shift in brain research. Science 294, 1021-1024 (2001).
28. Jaskiw, G. E., Karoum, F. K. & Weinberger, D. R. Persistent elevations in dopamine and its metabolites in the nucleus accumbens after mild subchronic stress in rats with ibotenic acid lesions of the medial prefrontal cortex. Brain Res. 534, 321-323 (1990).
29. Williams, G. V. & Goldman-Rakic, P. S. Modulation of memory fields by dopamine D1 receptors in prefrontal cortex. Nature 376, 572-575 (1995).
30. Schultz, W. Predictive reward signal of dopamine neurons. J. Neurophysiol. 80, 1-27 (1998).
31. Squire, L. R., Stark, C. E. & Clark, R. E. The medial temporal lobe. Annu. Rev. Neurosci. 27, 279-306 (2004).
32. Harrison, P. J. & Eastwood, S. L. Neuropathological studies of synaptic connectivity in the hippocampal formation in schizophrenia. Hippocampus 11, 508-519 (2001).
33. Heckers, S. Neuroimaging studies of the hippocampus in schizophrenia. Hippocampus 11, 520-528 (2001).
34. Heckers, S. et al. Impaired recruitment of the hippocampus during conscious recollection in schizophrenia. Nature Neurosci. 1, 318-323 (1998).
35. Simons, J. S. & Spiers, H. J. Prefrontal and medial temporal lobe interactions in long-term memory. Nature Rev. Neurosci. 4, 637-648 (2003).
36. Phillips, M. L., Drevets, W. C., Rauch, S. L. & Lane, R. Neurobiology of emotion perception I: the neural basis of normal emotion perception. Biol. Psychiatry 54, 504-514 (2003).
37. Weinberger, D. R., Berman, K. F., Suddath, R. & Torrey, E. F. Evidence of dysfunction of a prefrontal-limbic network in schizophrenia: a magnetic resonance imaging and regional cerebral blood flow study of discordant monozygotic twins. Am. J. Psychiatry 149, 890-897 (1992).
38. Bertolino, A. et al. Altered development of prefrontal neurons in rhesus monkeys with neonatal mesial temporo-limbic lesions: a proton magnetic resonance spectroscopic imaging study. Cereb. Cortex 7, 740-748 (1997).
39. Weinberger, D. R. Implications of normal brain development for the pathogenesis of schizophrenia. Arch. Gen. Psychiatry 44, 660-669 (1987).
40. Lewis, D. A. et al. Dopamine transporter immunoreactivity in monkey cerebral cortex: regional, laminar, and ultrastructural localization. J. Comp. Neurol. 432, 119-136 (2001).
41. Tunbridge, E. M., Bannerman, D. M., Sharp, T. & Harrison, P. J. Catechol-o-methyltransferase inhibition improves set-shifting performance and elevates stimulated dopamine release in the rat prefrontal cortex. J. Neurosci. 24, 5331-5335 (2004).
42. 58Met and beyond. Biol. Psychiatry 60, 141-151 (2006).
43. Owen, M. J., Williams, N. M. & O'Donovan, M. C. The molecular genetics of schizophrenia: new findings promise new insights. Mol. Psychiatry 9, 14-27 (2004).
44. Murphy, K. C. Schizophrenia and velo-cardio-facial syndrome. Lancet 359, 426-430 (2002).
45. Chen, J. et al. Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain. Am. J. Hum. Genet. 75, 807-821 (2004).
46. 108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc. Natl Acad. Sci. USA 98, 6917-6922 (2001).
47. 158Met genotype and schizophrenia. Arch. Gen. Psychiatry 60, 889-896 (2003).
48. 158-met genotype and individual variation in the brain response to amphetamine. Proc. Natl Acad. Sci. USA 100, 6186-6191 (2003).
49. Akil, M. et al. Catechol-O-methyltransferase genotype and dopamine regulation in the human brain. J. Neurosci. 23, 2008-2013 (2003).
50. Callicott, J. H. et al. Variation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia. Proc. Natl Acad. Sci. USA 102, 8627-8632 (2005).
51. Gothelf, D. et al. COMT genotype predicts longitudinal cognitive decline and psychosis in 22q11.2 deletion syndrome. Nature Neurosci. 8, 1500-1502 (2005).
52. Craddock, N., Owen, M. J. & O'Donovan, M. C. The catechol-O-methyl transferase (COMT) gene as a candidate for psychiatric phenotypes: evidence and lessons. Mol. Psychiatry 11, 446-458 (2006).
53. Fan, J. B. et al. Catechol-O-methyltransferase gene Val/Met functional polymorphism and risk of schizophrenia: a large-scale association study plus meta-analysis. Biol. Psychiatry 57, 139-144 (2005).
54. 158/108 Met) gene and schizophrenia: a meta-analysis of case-control studies. Mol. Psychiatry 10, 765-770 (2005).
55. Schott, B. H. et al. The dopaminergic midbrain participates in human episodic memory formation: evidence from genetic imaging. J. Neurosci. 26, 1407-1417 (2006).
56. Cohen, M. X., Young, J., Baek, J. M., Kessler, C. & Ranganath, C. Individual differences in extraversion and dopamine genetics predict neural reward responses. Brain Res. Cogn Brain Res. 25, 851-861 (2005).
57. Egan, M. F. et al. Variation in GRM3 affects cognition, prefrontal glutamate, and risk for schizophrenia. Proc. Natl Acad. Sci. USA 101, 12604-12609 (2004).
58. de Quervain, D. J. & Papassotiropoulos, A. Identification of a genetic cluster influencing memory performance and hippocampal activity in humans. Proc. Natl Acad. Sci. USA 103, 4270-4274 (2006).
59. Callicott, J. H. et al. Abnormal fMRI response of the dorsolateral prefrontal cortex in cognitively intact siblings of patients with schizophrenia. Am. J. Psychiatry 160, 709-719 (2003).
60. Cannon, T. D. et al. Association of DISC1/TRAX haplotypes with schizophrenia, reduced prefrontal gray matter, and impaired short- and long-term memory. Arch. Gen. Psychiatry 62, 1205-1213 (2005).
61. 158Met genotype. Biol. Psychiatry 4 Sept 2006 (doi:10.1016/j.biopsych.2006.03.078).
62. Shifman, S. et al. A highly significant association between a COMT haplotype and schizophrenia. Am. J. Hum. Genet. 71, 1296-1302 (2002).
63. Bray, N. J. et al. A haplotype implicated in schizophrenia susceptibility is associated with reduced COMT expression in human brain. Am. J. Hum. Genet. 73, 152-161 (2003).
64. Palmatier, M. A. et al. COMT haplotypes suggest P2 promoter region relevance for schizophrenia. Mol. Psychiatry 9, 859-870 (2004).
65. Meyer-Lindenberg, A. et al. Impact of complex genetic variation in COMT on human brain function. Mol. Psychiatry 20 June 2006 (doi:10.1038/ sj.mp.4001860).
66. Diaz-Asper, C. M. Weinberger, D. R. & Goldberg, T. E. Catechol-O-methyltransferase polymorphisms and some implications for cognitive therapeutics. NeuroRX 3, 97-105 (2006).
67. Devlin, B., Roeder, K. & Wasserman, L. Genomic control, a new approach to genetic-based association studies. Theor. Popul. Biol. 60, 155-166 (2001).
68. Laurienti, P. J., Burdette, J. H. & Maldjian, J. A. Separating neural processes using mixed event-related and epoch-based fMRI paradigms. J. Neurosci. Methods 131, 41-50 (2003).
69. Friedman, L. & Glover, G. H. Report on a multicenter fMRI quality assurance protocol. J. Magn. Reson. Imaging 23, 827-839 (2006).
70. Hariri, A. R. et al. Serotonin transporter genetic variation and the response of the human amygdala. Science 297, 400-403 (2002).
71. Friston, K. J. et al. Classical and Bayesian inference in neuroimaging: theory. Neuroimage 16, 465-483 (2002).
72. Manji, H. K., Drevets, W. C. & Charney, D. S. The cellular neurobiology of depression. Nature Med. 7, 541-547 (2001).
73. Mayberg, H. S. Limbic-cortical dysregulation: a proposed model of depression. J. Neuropsychiatry Clin. Neurosci. 9, 471-481 (1997).
74. Drevets, W. C. et al. Subgenual prefrontal cortex abnormalities in mood disorders. Nature 386, 824-827 (1997).
75. Mayberg, H. S. et al. Reciprocal limbic-cortical function and negative mood: converging PET findings in depression and normal sadness. Am. J. Psychiatry 156, 675-682 (1999).
76. Paus, T. Primate anterior cingulate cortex: where motor control, drive and cognition interface. Nature Rev. Neurosci. 2, 417-424 (2001).
77. Stefanacci, L. & Amaral, D. G. Some observations on cortical inputs to the macaque monkey amygdala: an anterograde tracing study. J. Comp. Neurol. 451, 301-323 (2002).
78. Sotres-Bayon, F., Bush, D. E. & LeDoux, J. E. Emotional perseveration: an update on prefrontal-amygdala interactions in fear extinction. Learn. Mem. 11, 525-535 (2004).
79. Nemeroff, C. B. & Owens, M. J. Treatment of mood disorders. Nature Neurosci. 5, S1068-S1070 (2002).
80. Lesch, K. P. et al. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 274, 1527-1531 (1996).
81. Caspi, A. et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 301, 386-389 (2003).
82. Hariri, A. R. et al. A susceptibility gene for affective disorders and the response of the human amygdala. Arch. Gen. Psychiatry 62, 146-152 (2005).
83. Heinz, A. et al. Amygdala-prefrontal coupling depends on a genetic variation of the serotonin transporter. Nature Neurosci. 8, 20-21 (2005).
84. Brown, S. M. et al. A regulatory variant of the human tryptophan hydroxylase-2 gene biases amygdala reactivity. Mol. Psychiatry 10, 884-888, 805 (2005).
85. Canli, T., Congdon, E., Gutknecht, L., Constable, R. T. & Lesch, K. P. Amygdala responsiveness is modulated by tryptophan hydroxylase-2 gene variation. J. Neural Transm. 112, 1479-1485 (2005).
86. Sabol, S. Z., Hu, S. & Hamer, D. A functional polymorphism in the monoamine oxidase A gene promoter. Hum. Genet. 103, 273-279 (1998).
87. Caspi, A. et al. Role of genotype in the cycle of violence in maltreated children. Science 297, 851-854 (2002).
88. Meyer-Lindenberg, A. et al. Neural mechanisms of genetic risk for impulsivity and violence in humans. Proc. Natl Acad. Sci. USA 103, 6269-6274 (2006).
89. Fan, J., Fossella, J., Sommer, T., Wu, Y. & Posner, M. I. Mapping the genetic variation of executive attention onto brain activity. Proc. Natl Acad. Sci. USA 100, 7406-7411 (2003).
90. Svenningsson, P. et al. DARPP-32: an integrator of neurotransmission. Annu. Rev. Pharmacol. Toxicol. 44, 269-296 (2004).
91. Weinberger, D. R. et al. Variation in PPP1R1B predicts risk for schizophrenia, cognitive function, and gene expression in brain. Am. J. Med. Genet. B Neuropsychiatr. Genet. 138B, 139-140 (2005).
92. Meyer-Lindenberg, A. et al. Neural mechanisms of genetic risk for impulsivity and violence in humans. Proc. Natl Acad. Sci. USA 103, 6269-6274 (2006).
93. Freedman, R. et al. Linkage of a neurophysiological deficit in schizophrenia to a chromosome 15 locus. Proc. Natl Acad. Sci. USA 94, 587-592 (1997).
94. Goldman-Rakic, P. S., Muly, E. C. & Williams, G. V. D1 receptors in prefrontal cells and circuits. Brain Res. Brain Res. Rev. 31, 295-301 (2000).
95. Seamans, J. K., Gorelova, N., Durstewitz, D. & Yang, C. R. Bidirectional dopamine modulation of GABAergic inhibition in prefrontal cortical pyramidal neurons. J. Neurosci. 21, 3628-3638 (2001).