| Summary |
Aiming to investigate the functionality of an NOS1 promoter repeat length variation (NOS1 Ex1f variable number tandem repeat [VNTR]) and to test whether it is associated with phenotypes relevant to impulsivity, they designed molecular biological studies to assess the cellular consequences of NOS1 Ex1f VNTR; association studies were conducted to investigate the impact of this genetic variant on impulsivity; imaging genetics was applied to determine whether the polymorphism is functional on a neurobiological level. More than 3200 subjects were included in the association study: 1954 controls, 403 patients with personality disorder, 383 patients with adult attention-deficit/hyperactivity disorder (ADHD), 151 with familial ADHD, 189 suicide attempters, and 182 criminal offenders. A novel functional promoter polymorphismin NOS1 was associated with traits related to impulsivity, including hyperactive and aggressive behaviors. Specifically, the short repeat variant wasmore frequent in adult ADHD, cluster B personality disorder, and autoaggressive and heteroaggressive behavior. This short variant came along with decreased transcriptional activity of the NOS1 exon 1f promoter and alterations in the neuronal transcriptome including RGS4 and GRIN1. On a systems level, it was associated with hypoactivation of the anterior cingulate cortex, which is involved in the processing of emotion and reward in behavioral control. |
| Total Sample |
More than 3200 subjects were included in the association study: 1954 controls, 403 patients with personality disorder, 383 patients with adult attention-deficit/hyperactivity disorder (aADHD), 151 with familial ADHD (fADHD), 189 suicide attempters, and 182 criminal offenders. |
| Sample Collection |
All subjects were white |
| Diagnosis Description |
The adult ADHD (aADHD) group consisted of inpatients and outpatients of the Department of Psychiatry, University of Wurzburg, referred for diagnostic assessment and treatment of aADHD and examined with the SCID-I. Inclusion criteria were aADHD according to DSM-IV, onset before the age of 7 years, lifelong persistence, current diagnosis, and age at recruitment between 18 and 65 years. Exclusion criteria were the appearance of symptoms restricted to the duration of any other Axis I disorder; current diagnosis of active alcohol or other drug abuse or dependence; lifetime diagnosis of bipolar I disorder, schizophrenia, or any other psychotic disorder; and mental retardation (IQ<80). The familial ADHD (fADHD) group consisted of inpatients and outpatients referred to the Department of Child and Adolescent Psychiatry, University of Wurzburg. Included children were characterized by standardized full interview (Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version) with a parent and met DSM-IV criteria for ADHD. Exclusion criteria were birth weight less than 2000g, IQ lower than 85, neurologic or severe somatic disorder, drug abuse, and autistic disorder. Control A group included a total of 640 subjects:284 were healthy blood donors originating from the Wurzburg area who were not screened for psychiatric disorders; however, all participants were free of medication. An additional 356 individuals were recruited and screened for absence of psychiatric disorders. Control B group consisted of 1314 unrelated healthy volunteers randomly selected from the general population of Munich. Subjects with neuropsychiatric disorders or with firstdegree relatives with such disorders were excluded by the Structured Clinical Interview for DSM-IV (SCID-I and SCID-II) and the Family History Assessment Module. |
| Technique |
For detailed information of methods and techniques about genotyping, microarray expression, reporter gene assays, and eletrophysiologic examinations, please refer to the original publication. |
| Analysis Method |
Association of NOS1 genotype with aADHD were tested by means of X2 tests comparing NOS1 genotype frequencies in the aADHD sample with those in the fully psychiatrically screened control sample B. The association remained significant when tested against control sample A and the combined control sample. To control for comorbidity with cluster B PD, a second analysis was performed comparing only those aADHD participants who did not exhibit a cluster B PD (n=194). A family-based association test, valid for families with an arbitrary number of affected children, was performed by using a permutation test implemented in FAMHAP software |
| Result Description |
Both examined control populations displayed an almost identical distribution of NOS1 Ex1f VNTR (P-value=0.33), whereas a consistent significant excess of short alleles was detected in adequately powered patient populations. On a categorical level, short NOS1 Ex1f VNTR alleles were not associated with anxious-avoidant cluster C PD (P-value=0.33), but were associated with the presence of emotional-dramatic cluster B PD (P-value=0.01), especially histrionic (P-value=0.009) PD, and with the presence of aADHD (P-value=0.001). Because in the latter sample a high comorbidity with cluster B PD has been reported, they investigated in a separate, family-based sample of children with ADHD (n=355) whether the short NOS1 Ex1f VNTR allele contributes to genetic risk toward ADHD per se. However, short NOS1 Ex1f VNTR alleles were not preferentially transmitted to affected offspring (P-value=0.39). They then controlled for absence or presence of cluster B PD in aADHD; after exclusion of all aADHD participants with cluster B PD, the association of NOS1 with aADHD remained significant (P-value=0.04), arguing for the notion that the polymorphism conveys risk for persistence of ADHD into adulthood independently of comorbid PD. In the forensic sample, childhood adversity was controlled for because it was shown to be a risk factor for laterlife violence. Short NOS1 Ex1f VNTR alleles were independently associated with later-life violent crime. Finally, suicide attempters also carried short alleles more frequently (P-value=0.02). |
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