Unit:
Τομέας Κοινωνικής Ιατρικής - Ψυχιατρικής και ΝευρολογίαςLibrary of the School of Health Sciences
Author:
Χατζημανώλης Αλέξανδρος
Dissertation committee:
Αναπλ. Καθηγητής Νικόλαος Στεφανής, Αναπλ. Καθηγητής Νικόλαος Σμυρνής, Αναπλ. Καγηγήτρια Κορνηλία Πουλοπούλου
Original Title:
Ανίχνευση γενετικών επιδράσεων στην εκδήλωση ενδοφαινοτύπων για μείζονες ψυχικές διαταραχές στο γενικό πληθυσμό
Translated title:
Identification of genetic effects for endophenotypes of mental disorders in the general population
Summary:
Impairment of cognitive functioning is often observed among patients with
psychiatric disorders and represents an endophenotype with potential usefulness
for genetic studies. It has been hypothesized that psychotic disorders (i.e.
schizophrenia, bipolar disorder) and cognitive ability share common genetic
determinants. In the present study, an association between known genetic risk
variants for psychotic disorders and cognitive function was investigated in a
large sample of young healthy adults from the Greek general population (n=2130,
mean age: 22 years), recruited by the Athens Study of Psychosis and Incidence
of Schizophrenia (ASPIS). Moreover, a genome-wide association study (GWAS) was
conducted for candidate cognitive and behavioral endophenotypes of psychotic
disorders and attention-deficit hyperactivity disorder (ADHD). A total of ~5.5M
single nucleotide polymorphisms (SNPs) across the genome were examined after
appropriate genotype imputation using the 1000 Genomes Project panel as a
reference. Linear regression models adjusted for age and years of education
were applied to test for genotype - phenotype associations. Follow-up
replication analyses were attempted in an independent cohort of young males
(n=825) and a clinical sample of 580 patients with schizophrenia with
comparable cognitive measures in order to validate top ranked genetic
associations. Genome-wide complex trait (GCTA) analysis was also performed to
estimate the heritability of all phenotypes based on genome-wide SNP data. A
polygenic risk score derived from multiple common SNPs increasing schizophrenia
and ADHD susceptibility, as shown in large GWAS meta-analyses, was
significantly correlated with weaker cognitive function in the ASPIS, in
particular working memory (WM) performance. Substantial heritability estimates
were noted for WM, sustained attention and visual fixation phenotypes. In
addition, SNPs within genes expressed in the human brain and involved in
synaptic neurotransmission were significantly associated with cognitive
performance and personality traits, such as schizotypy and impulsivity in young
adulthood. Summarizing, in accordance with previously reported findings from
healthy populations, these results suggest that common genetic variation
explains a significant proportion of cognitive phenotypic variance in the
general population and that genetic risk variation for psychosis and ADHD
influence human cognition. Further, the GWAS results implicated biologically
relevant genetic loci encoding protein targets involved in synaptic functioning
that might affect cognitive ability and personality traits relevant to
psychotic disorders.
Keywords:
Cognitive function, Endophenotype, Polymorphism, Gene, Schizophrenia
Number of references:
250
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