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Responsabile: Dott.ssa Sheila Ulivi
Il panico è una condizione psichiatrica grave e potenzialmente invalidante caratterizzata da attacchi di panico inaspettati e la paura della loro ricorrenza o di gravi conseguenze. La patogenesi del panico è complessa, molto probabilmente coinvolge fattori psicologici, biologici ed evolutivi collegati alla sopravvivenza. L'idea di base è di analizzare individui scelti da popolazioni geneticamente isolate e alcuni gruppi di pazienti provenienti da diverse regioni italiane per i quali i dati fenotipici e di genotipizzazione sono già disponibili. L'applicazione di nuove tecnologie, come Whole Genome Sequencing (WGS) in popolazioni omogenee come quelle disponibili, aumenterà il processo d’identificazione di varianti associate al panico.
Background and Significance
Panic disorder is a serious and potentially disabling psychiatric condition characterized by unexpected panic attacks and fear of their recurrence or harmful consequences.
Epidemiological surveys have shown lifetime prevalence of panic disorder with or without agoraphobia at 3.4-4.7% with female preponderance, typically young adult age of onset and major functional impairment.
The pathogenesis of panic disorder is complex, most likely involving psychological, biological, and survival-related evolutionary factors. Several psychobiological models have been proposed to explain the onset and development of panic disorder, but it is likely that most cases have a complex genetic basis.
Twin studies have confirmed that additive genetic factors explain approximately 30-46% of the variance in the disease with an heritability estimated to be approximately 48%.
To date more than 350 candidate genes and an overall numberof 1000 DNA polymorphisms have been analyzed. Genes mainly belong to opioid, immune, neurotrophic and hormonal systems/pathways.
An approach to reduce underlying genetic complexity is the use of isolated populations originated from a small number of founder couples. Due to increased inbreeding and genetic drift in isolates, certain alleles will be present more frequently in the population, while others are lost, increasing genetic homogeneity.
Specific aims
Aim 1: Definition, using Whole Genome Sequencing (WGS), of most of the genetic variation of the INGI Friuli Venezia Giulia project to also identify novel and rare variants not yet described in large sequencing projects like 1000G
Aim 2: To combine WGS data together with those existing ones (i.e. genotyping data arising both from Illumina 700K and Illumina Exome Arrays).
Aim 3: To perform a Genome Wide Association analysis cases coming from INGI-FVG using several different model (overdominant, dominant, recessive, additive) and to replicate them in outbred populations.
Hypothesis
The basic idea is to take the advantage of the availability of a unique source of individuals characterized by a series of genetically isolated populations and some clusters of patients from different Italian regions for which geneotyping and phneotyping data are already available. Applying new technologies such as WGS in homogenous populations like those available will spee up the process of identifying variants (including rare and novel ones) underlying panic disorder, Briefly, our Genome Wide Association Study (GWAS) will be based on genetic information arising from high-density (HD) SNPs arrays (Illumina 700K + IlluminaExome) and WGS data. statistical analysis, which will use stratification detection tools and stratified statistical methods to control for genetic variation across the different geographical areas.
Preliminary data
A total number of >1800 DNAs have been genotyped (Illumina 370k or OMNI arrays). All participants were investigated with the Structured Clinical Interview for DSM-IV-TR Disorders (SCID-I). We constructed an algorithm to systematically review the literature and to identify candidate genes among those already found associated in panic disorder. The cases were 10% of the participants. We performed a region association study obtained an association with the progesterone receptor gene (PGR; p= 5.5*10-4). The found a haplotype resulted associated with panic disorder (p=0.00267). In particular if the individual is a female and presents at least one copy of the haplotype CTTGA has a major probability (Odds Ratio=0.297) to be protected by panic disorder. WGS studies are in progress and so far more data from 250 individuals are available.
Materials and Methods
WGS will be carried out using internal and external facilities. All sequenced variants will be imputed into the remaining genotyped populations using IMPUTE2 or similar algorithms. Because of the population structure and the availability of large genealogies, long shared haplotypes can be identified which will allow very high accuracy imputation into genotyped samples. Variants will be analyzed in our cohort for association for the panic disorder, using statistical tests appropriate for genetic isolates. Results will be compared with cohorts from the general population in Italy when available.
Impact and Translational Implications
Our preliminary findings are promising because allow to focus on broad phenotypes defined by comorbidity or intermediate phenotypes. The GWAs offers the opportunity to extend molecular genetic analysis by introducing these techniques, and develop tailor-made medical re-sequencing approaches for the gene identification and diagnosis of heterogeneous disorders. At the end of the project we expect to have defined a set of variations that could be translated into molecular diagnostics.