Agreeableness

XYY [HGL]
   In the 1960's, several studies identified an increased frequency of men with the XYY genotype in prison populations.  These observations led to the hypothesis that the extra Y chromosome caused aggressive and violent behavior.  See, e.g., Jacobs, 1965; Hook, 1973.  The association between the XYY genotype and antisocial behavior has been hotly debated.  A comprehensive study in 1976 of males born between 1944 and 1947 in Denmark found no support for the hypothesis.  Witkins et al., Science, 193: 547-555, 1976.  Instead, they found that in the general population XYY men did not differ from genotypically normal XY men in violent or criminal behavior.  However, the found that XYY men were more likely to be taller than their normal counterparts.    In addition, they scored significantly and substantially lower on intelligence tests than normal XY men.  Schiavi et al., Arch. Gen.  Psychiatry, 41:93-99, 1984.

alpha-adrenergic receptor, type 2C (alpha-AR2C) [GE]
    The alpha-adrenergic receptor, type 2C, was targeted and inactivated in transgenic mice.  These mice display an enhanced startle reflex and shortened attack latency in the isolation aggression test.  Sallinen et al., J. Neurosci., 18:3035-3042, 1998.

brain estrogen receptor [GE]
    Steroid hormones regulate the development of sexually dimorphic brain function and behavior.  Mice lacking the estrogen receptor were created by genetic engineering.  Engineered male mice, although infertile, displayed normal female mounting behavior.  Aggressive behaviors and male-typical offensive behaviors were also markedly reduced.  Ogawa et al., Proc. Natl. Acad. Sci., 94(4):1476-1481, 1997.

calmodulin (alpha-calcium-calmodulin-dependent kinase II, CaMKII) [GE]
    Mice deficient in the calmodulin gene (alpha-calcium-calmodulin-dependent kinase II, CaMKII) were engineered.  Heterozygotes showed a decreased fear response and increase in defensive aggression.  The homozygotes were abnormal in all behavioral paradigms tested.  Chen et al., Science, 266:291-294, 1994.  See, also Entry under Openness.

catechol-O-methyltransferase (COMT) [GE]
    Catechol-O-methyltransferase (COMT) is involved in the metabolic degradation of catecholamines (e.g., dopamine, epinephrine, and norepinephrine).  Heterozygous COMT-deficient male mice exhibited increased aggressive behaviors.  Gogos et al., Proc. Natl. Acad. Sci., 95:9991-9996, 1998.

glutamic acid decarboxylase, 65 kDa isoform (GAD65) [GE]
    Glutamic acid decarboxylase (GAD) is involved in the synthesis of GABA, a neurotransmitter in the CNS.  Mice with an inactivated GAD gene showed abnormal behaviors, including increased anxiety-like behavior and reduced intermale aggression.  Stork et al., Brain Res., 865:45-58, 2000.  See, also entry under Neuroticism.

monoamine oxidase A (MAOA) [HGL] [GE]
    MAOA is involved in the metabolism of the monoamine neurotransmitters dopamine, serotonin, epinephrine, and norepinephrine. MAO inhibitors are used to treat depression disorders.  A Dutch family was identified with a recessive X-linked condition characterized by mild mental retardation and aggressive, sometimes violent, behavior.  Four generations of affected males were identified.   The locus of the disorder was mapped to the p11-21 position on the X-chromosome, coincident with the locus of an MAOA gene.  Consistent with an MAOA gene defect, affected males displayed a marked disturbance in monoamine metabolism.  Brunner et al., A. J. Hum. Genet., 52:1032-1-39, 1993; Morell, Science, 260:1722-1723, 1993.  A line of transgenic mice were created in which the MAOA gene was deleted.  These mice displayed higher brain concentrations of serotonin and epinephrine. Pups showed a number of phenotypes associated with the MAO deficiency, including trembling, difficulty in righting and fearfulness.  Adult males showed enhanced aggression.  Cases et al., Science, 268:1763-1766, 1995.  A study of 110 men showed an association between polymorphisms in the MAOA gene and aggressiveness, impulse control, and cental nervous system responsiveness. Two types of polymorphisms were studied:  a 30-base pair VNTR (variable nucleotide tandem repeat) in the promoter region and a dinucleotide repeat in intron 2.  Manuck et al., Psychiatry Res., 95:9-23, 2000.

nitric oxide synthase, endothelial isoform (eNOS) [GE]
    Mice with targeted deletions of the endothelial isoform of nitric oxide synthase (eNOS) were less aggressive compared with wild-type animals as measured by the resident-intruder model of aggression.  Mice homozygous-deficient for the eNOS gene were hypertensive, as well, but such hypertension did not appear to be responsible for the diminished aggression since reduction of blood pressure with drugs did not alter the prevalence of aggression.  J. Neurosci. (Online), 19:RC30, 1999.

nitric oxide syntheses, neuronal isoform (nNOS) [GE]
    Nitric oxide acts as a neural messenger in both the central and peripheral nervous systems.  Male mice in which the neuronal isoform of nNOS has been functionally disrupted show inappropriate sexual behavior and exhibit an increase in the number and duration of aggressive encounters compared to wild-type, control, animals when tested in a variety of paradigms used to test rodent aggression. This aggressive behavior has only been observed in nNOS mutant mice; nNOS deficient female mice, like female wild-type, exhibit little or no aggression.  Studies showed that reducing systemic testosterone by castration reduced aggression in both wild-type and mutant nNOS males to equivalent low levels. Testosterone replacement restored aggression to precastration levels in both genotypes. These data provide evidence that increased aggressive behavior of mutant nNOS mice, like aggression in wild-type mice, is testosterone-dependent. Kriegsfeld et al., Brain Res., 769(1):66-70, 1997; Demas et al., Mol. Med., 3(9):610-616, 1997; Nelson et al., Nature, 378(6555):383-386, 1995.

NK-1 [GE]
    The NK-1 gene which codes for the substance P receptor was functionally disrupted in transgenic mice. Knockout mice were considerably less aggressive than wild-type mice when exposed to wild-type male mice communally housed. De Filipe et al., Nature, 392:394-397, 1998.

regulator of G-protein signaling-2 (rgs2) [GE]
    Regulator of G-protein signaling-2 (rgs2) is a member of a family of genes which accelerate the GTPase activity of G-proteins.  They contain a conserved RGS domain of about 120 amino acids.  rgs2 is up-regulated in the central nervous system after stimuli which evoke long-term neuronal plasticity.  To investigate its in vivo role, rgs2-deficient mice were generated.  The rgs2 deficieny had no apparent effect on motor responses, exploratory behavior, spatial learning, or memory.  However, mice lacking the rgs2 gene completely (rgs2-/rgs2-) showed reduced male aggression when compared to heterozygous (rgs2-/rgs2+) littermates.  The aggressive response of female mice deficient in rgs2 was normal.  In addition to aggression, rgs2-deficient mice showed increased anxiety as compared to heterozygous littermates (data comparing males and females in the anxiety test were not presented.)  Differences in the CA1 hippocampal neursons were observed in rgs-deficient mice as compared to controls.  Oliveira-dos-Santos et al., Proc. Natl. Acad. Sci., 97:12272-12277, 2000.  See, also, entry under Neuroticism.

serotonin receptor, type 1B (5-HT1B) [GE]
    Mice were generated which lack the 5-HT1B receptor. When confronted with an intruder, isolated mutant mice attacked the intruder faster and more intensely than wild-type mice, suggesting an involvement of 5-HT1B receptors in the modulation of aggressive behavior. These data are consistent with other findings that certain impulsive aggressive behaviors are associated with deficits in central serotonin. Ramboz et al., Behav. Brain. Res., 73(1-2):305-312, 1996.

serotonin transporter (5-HTT or SERT) [HGL]
    A common 44-base pair polymorphism in the promoter of the serotonin transporter is associated with affective illness and anxiety disorders.  The polymorphism has been designated long (L) and short (S), depending on whether the insertion is present or absent in the promoter region.  The S allele is less active than the L allele.  The frequency of the S allele was higher in type 2 alcoholics than in type 1 alcoholics and healthy controls.  Type 2 alcoholics display early onset alcholism associated with antisocial personality disorder and impulsive, habitually violent behavior.  Type 1 alcoholism is late-onset and non-violent.  Hallikainen et al., Mol. Psychiatry, 4:385-388, 1999.

tryptophan hydroxylase (TPH) [HGL]
    Tryptophan hydroxylase (TPH) is involved in the biosynthesis of serotonin.  A polymorphism was located in intron 7 of the TPH gene.  A population of men and women were analyzed for aggression and anger-related traits of personality, and the presence of the U and L polymorphism of the TPH gene.  Individuals having a U allele of the TPH gene scored significantly higher on measures of aggression and tendency to experience unprovoked anger.  Such individuals were also more likely to outwardly express anger than individuals homozygous for the L allele.   Manuck et al., Biol. Psychiatry, 45:603-614, 1999.