Noomi O. Gregersen vart ph.d. við Aarhus Universitet
Hósdagin 10 september vardi Noomi Oddmarsdóttir Gregersen ph.d.ritgerð sína við Translational Neuropsychiatry Unit, Institut for Klinisk Medicin, Aarhus Universitet. Ritgerðin kallast "Identification and analyses of genetic risk factors for panic disorder".
Tær undirliggjandi orsøkirnar til og sjúkumekanismurnar handan panikangist eru ikki greiðar í smálutum enn, men ættarbregði hava ein munandi leiklut í menning av sjúkuni. Í ritgerð síni hevur Noomi O. Gregersen eyðmerkt og greinað samanhangin millum genetiskar variantar og panikangist. Kanningin fevnir um sjúklingar og frískar kontrolpersónar úr Føroyum, Danmark og Týsklandi. Verkætlanin hevur eyðmerkt vandavariantar, sum í ávísan mun hava lut í menningini av panikangist. Ritgerðin hevur á hendan hátt lagt afturat verandi vitan um og fatan av genetisku samansetingini av panikangist. Granskingarúrslitini kunnu í framtíðini verða við til at geva eina betri fatan av sjúkumekanismunum, og tí gera tað møguligt at finna betri fyribyrging og viðgerð.
Verjan gekk sera væl. Metingarfólkini løgdu millum annað dent á, at granskingarúrslitini í hesi verkætlanini kunnu koma at hava stóran týdning í fatanini av panikangist í framtíðini.
Verkætlanin er lutvíst fíggjað úr Granskingargrunninum.
Vegleiðarar hava verið Ole Mors, professari, Henriette Nørmølle Buttenschøn, ph.d, og Anders Dupont Børglum , professari, øll knýtt at The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH ,og August Gabriel Wang, MD, yvirlækni og kliniskur lektari á Institut for Klinisk Medicin, Region Hovedstadens Psykiatri.
Í metingarnevndini vóru
Anders Lade Nielsen, professari , Department of Biomedicine, Aarhus Universitet, formaður
Andreas Reif, professari, Dept. of Psychiatry, Psychosomatics and Psychotherapy, University Hospital Frankfurt am Main - Goethe University
Lene Christansen, professari, Epidemiology, Biostatistics and Biodemography, Clinical Biochemistry, The Danish Twin Registry, Human Genetics, Danish Aging Research Center
Gregers Wegener, profesari, Translational Neuropsychiatry Unit, Dept. of Clinical Medicine, Aarhus Universitet
Les um verkætlanina í Stuðulsyvirlitinum
og um Noomi O. Gregersen í Heilagrunninum
Á myndini eru August G. Wang, vegleiðari, og Noomi O. Gregersen ph.d. beint eftir verjuna.
Summary
Panic disorder (PD) is characterized by recurrent and unprovoked panic attacks, which often results in substantial distress and impairment. The mechanism underlying PD is largely unknown, however, there is a substantial evidence for a genetic contribution in the aetiology as family and twin studies demonstrate a complex mode of inheritance and a heritability near 40 %. The genetic composition of PD is unknown, however, like other complex disorders, the genetic architecture is likely to involve common variants with small effect and rare variants with larger effect. Identifying genetic variants involved in PD will increase the understanding of the biological disease mechanisms of this disorder.
The aim of the present thesis was to identify common and rare genetic variants contributing to the risk of PD by analysing cases with PD and controls from the isolated population of the Faroe Islands. Due to founder effect and genetic drift isolated populations are expected to be genetically homogeneous and therefore ideal for mapping risk variants for complex disorders. Especially the potential enrichment of rare variants in isolated populations may be considered beneficial to increase the power to detect rare variants. Identified risk variants may then subsequently be verified in out-bred populations.
We applied two different approaches for identifying and analysing genetic risk variants for PD. Using a hypothesis driven approach common variants within selected candidate-genes were analysed for association with PD. In a hypothesis free approach we performed whole-exome sequencing in an attempt to identify and analyse both common and rare variants for PD.
Six candidate-genes (ACCN1, TMEM132E, TMEM98, SNAPC2, MAP2K7 and LRRC8E) were selected based on the results from a previous study investigating 13 cases and 43 controls from the isolated population of the Faroe Islands, identifying candidate regions for PD to be located within chromosome 17q11.2-q12 and 19p13.2. A total of 92 single nucleotide polymorphisms (SNPs) were successfully analysed for association with PD using a Faroese and a Danish case-control cohort (paper I-III). In total 279 cases and 807 controls were analysed. Five of these genes (40 SNPs) were further analysed in a German cohort of 232 cases and 222 controls (paper II and III). Our results indicate that five of the analysed genes (ACCN1, TMEM132E, SNAPC2, MAP2K7 and LRRC8E) may contribute moderately towards the risk of developing PD.
A Faroese cohort consisting of 54 cases with PD and 211 controls were whole-exome sequenced. After various quality considerations a total of 122.511 genetic variants were accepted for further analysis. Variants were tested for associations with PD by performing single-variant analysis. Additionally, we performed gene-based analysis of all functional deleterious variants with a minor allele frequency below 5 %. No genome-wide significant association was observed but several variants were nominal associated with PD. Likewise no exome-wide significant association was observed, however, the gene DGKH, which previously has been associated with other mental disorders, was the most strongly associated gene. Additionally, we demonstrate that potential enrichment of risk variants rarely seen in more out-bred European populations is likely in the Faroese population (paper IV). In future studies, we will investigate the most significantly associated variants in out-bred populations.
Identifying genetic risk factors for PD is the first step towards elucidating the biological disease mechanisms involved in the aetiology of PD. This thesis contributes to the present knowledge and understanding of the genetic architecture of PD.