טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentRosenberg Shai
SubjectPopulation Genetic Analysis of DNA Sequence Variation at
the MAOA Locus and Relation to Quantitative
Behavioral Traits
DepartmentDepartment of Medicine
Supervisors Professor Karl Skorecki
Professor Sara Selig


Abstract

Monoamine oxidase A (MAOA) catalyzes the oxidative deamination of biogenic amines including neurotransmitters, mainly norepinephrine and serotonin in the brain and peripheral tissues. A nonsense mutation in the gene was shown to be involved in a rare X-linked behavioral syndrome, which includes impaired impulse control, aggression and borderline mental retardation (Brunner syndrome). Several recent studies have shown the association of a VNTR polymorphism in the gene promoter with various pathological behavioral traits. In the present study the association of MAOA genetic variation with a large set of quantitative behavioral traits in normal individuals has been examined. Sequencing of five regions totaling 18.8kb and spanning 90kb of the MAOA gene was carried out in 56 male individuals, in order to identify polymorphic sites and to investigate population genetic characteristics of MAOA DNA sequence variation. Forty polymorphic sites were identified. Initial analysis revealed that there was no evidence of linkage disequilibrium decay across this genetic locus, despite high levels of recombination. This pattern is consistent with population structure or positive selection acting on the gene, and indeed a variety of indices were consistent with positive selection and specifically, selective sweep acting on the gene.  Thereafter, DNA samples from 421 unrelated males were genotyped for 14 of the identified SNPs in the resequencing protocol, and for the VNTR at the MAOA promoter. An additional 16 SNPs were genotyped at genomic neutral sites across the X chromosome to serve as a genomic control for possible false positive associations due to population structure. Behavioral traits were measured using the NEO psychometric questionnaire, which is based on a 5-axis model of personality, and consists of 30 different quantitative traits. There was a robust association of the A2 (“straightforwardness”) facet with common allelic variants at the promoter VNTR.  Most of the tested traits were not associated with the VNTR, despite reasonable power, thus demonstrating that the VNTR influence on quantitative behavioral traits in normal males may be very specific. In contrast, several traits of the C (“conscientiousness”) axis were associated with less common SNP-defined haplotypes. Hence, it appears that common genetic variation at the VNTR contributes to the behavioral attribute of “straightforwardness”, while rare haplotypes defined by SNPs downstream of the transcription start site may contribute to “conscientiousness”. This study is used to address the validation, interpretation and limitation of genetic association studies of quantitative behavioral traits.