Am. J. Hum. Genet. 65:593–598, 1999 593 PSYCHIATRIC GENETICS ’99 Monoamine Oxidase in Neuropsychiatry and Behavior J. C. Shih 1,2 and R. F. Thompson 3 1 Department of Molecular Pharmacology and Toxicology and 2 Department of Cell and Neurobiology and 3 Program in Neuroscience, University of Southern California, Los Angeles Monoamine oxidase (MAO) catalyzes the oxidative de- amination of a number of biogenic amines, including the key neurotransmitters serotonin (5-HT), norepinephrine (NE), and dopamine (DA) and the neuromodulator phenylethylamine (PEA). Two forms of MAO, desig- nated “MAO A” and “MAO B,” have been identified on the basis of biochemical properties and, subsequently, by cloning the relevant genes. Of the two, MAO A ex- hibits a higher affinity for 5-HT and NE and for the inhibitor clorgyline (Johnston 1968), whereas MAO B has a higher affinity for PEA, benzylamine, and the in- hibitor deprenyl (Knoll and Magyar 1972). DA is a sub- strate for both MAO A and MAO B. Although most tissues express both isoenzymes, human placenta and fibroblasts express predominantly MAO A, and platelets and lymphocytes express only MAO B (for review, see Shih et al. 1999). The ability of the MAOs to catabolize neurotrans- mitters has made these enzymes attractive candidates in the study of neurological diseases and psychiatric and behavioral traits. Indeed, even before the genes for MAO A and B were cloned, the role of MAO B in psychiatric disorders was widely studied. Platelets, which are easily obtained and lack MAO A expression, were the cell type of choice for much of this work. Low platelet MAO B activity has been associated with bipolar disorder, sui- cidal behavior, and alcoholism (Devor et al. 1993), as well as with sensation seeking and poor impulse control (Oreland 1993; Holschneider and Shih 1998). However, much of this biochemical work may need to be revisited, given the recent finding that smoking inhibits both MAO A activity and MAO B activity (Fowler et al. 1996a, 1996b). For instance, after correcting for the effect of smoking, Simpson et al. (1999) determined that MAO Received May 11, 1999; accepted for publication July 21, 1999; electronically published August 6, 1999. Address for correspondence and reprints: Dr. Jean Chen Shih, Phar- maceutical Sciences Center, Room 528, Department of Molecular Pharmacology and Toxicology, University of Southern California, Los Angeles CA 90033. E-mail: jcshih@hsc.usc.edu This article represents the opinion of the authors and has not been peer reviewed.  1999 by The American Society of Human Genetics. All rights reserved. 0002-9297/1999/6303-0003$02.00 B activity is not significantly reduced in schizophrenics. With the successful cloning of human liver MAO A and B, Bach et al. (1988) demonstrated that MAO A and B are distinct, but closely related, X-linked genes (Shih 1991). The MAO A and MAO B genomic sequences (Grimsby et al. 1991; Chen et al. 1992) and promoters (Zhu et al. 1992; Zhu and Shih 1997) have been studied extensively in the pursuit of polymorphisms that might show these genes to be associated with psychiatric dis- orders and behaviors. Perhaps the most intriguing find- ing to emerge to date implicates MAO A in the control of aggressive behavior in humans, a finding that we and our collaborators have pursued in a knockout-mouse model. Deletion of MAOA and MAOB in Norrie disease The gene for Norrie disease (ND) and the genes MAOA and MAOB are arranged in tandem on human Xp11.2-11.4 (Chen et al. 1995). Deletion of ND is some- times accompanied by deletion of one or both of the MAO genes and causes congenital blindness due to the disrupted development and degeneration of the neuro- retina (Berger et al. 1992). More than one-third of ND patients also develop progressive hearing loss and man- ifest mental retardation or psychoses (Sims et al. 1989). Two such patients, studied in detail by Sims et al. (1989) and Lenders et al. (1996), lack detectable MAO B ac- tivity in their platelets and do not express MAO A mRNA in their fibroblasts, and they show elevated plasma and urine levels of NE, DA, 5-HT, and PEA. Two brothers with a contiguous-gene deletion encom- passing ND and MAO B show an increase in urinary PEA levels, but their levels of 5-HT, NE, and DA are normal (Lenders et al. 1996). These neurochemical changes are consistent with the findings in Maoa-knock- out (Cases et al. 1995) and Maob-knockout (Grimsby et al. 1997) mice. The clearest genetic evidence that the MAOs regulate human behavior comes from the work of Brunner et al. (1993a, 1993b), who studied a Dutch family in which eight males manifest a complex behavioral syndrome that includes borderline mental retardation and impul- sive aggression. Sequencing of the MAOA gene showed,