An integrative analysis of genetics, brain structure, and childhood trauma in antipsychotic treatment response : toward a unified view of treatment outcome in schizophrenia

Frickel, Emma (2020-03)

Thesis (MScAgric)--Stellenbosch University, 2020.

Thesis

ENGLISH ABSTRACT: Schizophrenia is a debilitating neuropsychiatric disorder affecting approximately 1% of the global population. Unfortunately, antipsychotic treatment is ineffective in 50% of patients. The complex, heterogeneous and multifactorial nature of antipsychotic response presents a challenge with respect to elucidating the underlying mechanisms. Although genetic, neuroimaging, and clinical studies of antipsychotic response have shown much progress and potential, clinically actionable findings remain incredibly limited. This has hindered the progress toward more personalised treatment approaches, highlighting the necessity of implementing larger cohorts and more integrated approaches in antipsychotic treatment response studies. Genetic and brain structural variation has been widely implicated in antipsychotic response, and there is emerging evidence for a role of childhood trauma in differential treatment outcomes. Although imaging genetics and geneenvironment interaction (GxE) studies have begun to disentangle the underlying relationships between these variables, studies of this nature in antipsychotic response remain scarce. This study aimed to investigate the interplay between genetics, brain structure, childhood trauma, and antipsychotic response, using an integrative approach. This was done with a cohort of 103 first-episode schizophrenia patients treated with a long-acting injectable antipsychotic. Data was available for genome-wide variants, baseline regional brain volumes, childhood trauma severity, and treatment response. Candidate genes previously associated with both brain structure and antipsychotic response were selected from literature. From the available genotype data, variants within these genes were extracted and prioritised using a bioinformatics pipeline. Next, based on previous associations with antipsychotic response in literature, brain regions of interest (ROIs) were identified in the available neuroimaging data. Linear regression was used to conduct association analyses exploring the roles of ROIs in treatment response, childhood trauma in antipsychotic response/brain structure, imaging genetics in antipsychotic response, and imaging geneenvironment interactions in antipsychotic response. Ten genetic variants in CACNA1C, NRG1, and OXTR were significantly associated with antipsychotic response, after correction for multiple testing; ⍺=6.720×10-5 (additive model), ⍺=9.470×10-5 (genotypic model). Thirty-four significant associations with antipsychotic response were identified for GxE with childhood trauma and variants in CACNA1C, COMT, DISC1, DRD3, NRG1, and OXTR; ⍺=1.120×10-5 (additive model), ⍺=1.578×10-5 (genotypic model). None of the remaining association analyses yielded significant results, so an unadjusted threshold (⍺=0.05) was considered for the exploratory observation of imaging genetic and imaging gene-environment interaction trends of interest. Five GxE significantly associated with improved response to antipsychotics showed tentative trends for increased putamen and hippocampal volumes. Conversely, six GxE significantly associated with poorer treatment response showed trends for reduced volumes of the caudate, cortex, pallidum, putamen, subcortical grey matter, and total grey matter. These findings highlighted a trendlevel positive correlation between baseline ROI volumes and treatment response (i.e. larger ROI volumes and improved antipsychotic response, and vice versa). The tentative positive correlation between ROI volumes and antipsychotic response in the context of GxE suggests a mechanism through which the relationship between brain structure and antipsychotic response may be mediated. Overall, the novel significant associations, and trends of interest, provide support for the utility of integrated research approaches to more effectively disentangle relationships between underlying molecular mechanisms and heterogeneous treatment response phenotypes.

AFRIKAANSE OPSOMMING: Skisofrenie is 'n verswakkende neuropsigiatriese versteuring wat ongeveer 1% van die wêreldbevolking aantas. Ongelukkig is antipsigotiese behandeling oneffektief in ongeveer 50% van pasiënte. Die komplekse, heterogene en multifaktoriale aard van antipsigotiese reaksie bied 'n uitdaging met betrekking tot die toeligting van die onderliggende meganismes. Alhoewel genetiese, brein beelding en kliniese studies van antipsigotiese reaksie baie vooruitgang en potensiaal getoon het, bly kliniese werkbare bevindings ongelooflik beperk. Dit het die vordering na meer verpersoonlikte behandelingsbenaderings belemmer, en dit het die noodsaaklikheid van die implementering van groter kohorte en meer geïntegreerde benaderings in antipsigotiese behandelingsresponse uitgelig. Genetiese en breinstruktuurvariasie is bekend om betrokke te wees by antipsigotiese reaksie, en daar is opkomende bewyse vir die rol van kindertyd trauma in die differensiële uitkoms van behandeling. Alhoewel die beeldings genetika en gene-omgewing interaksie (GxE) studies begin het om die onderliggende verwantskappe tussen hierdie veranderlikes te ontrafel, bly studies van hierdie aard in antipsigotiese reaksie skaars. Hierdie studie mik om die wisselwerking tussen genetika, breinstruktuur, kindertyd trauma en antipsigotiese respons met behulp van 'n geïntegreerde benadering te ondersoek. 'n Groep van 103 pasiënte met die eerste episode van skisofrenie wat behandel is met 'n langwerkende inspuitbare antipsigotiese middle is gebruik vir hierdie studie. Data was beskikbaar vir genoomwye variante, basislyn streeksbreinvolumes, erns van kindertyd trauma en die respons van behandeling. Kandidaatgene wat voorheen met beide breinstruktuur en antipsigotiese respons geassosieer is, is uit die literatuur gekies. Uit die beskikbare genotipe-data is variante binne hierdie gene onttrek en geprioritiseer met behulp van 'n bioinformatika-pyplyn. Volgende, op grond van vorige assosiasies met antipsigotiese respons in die literatuur, is breinstreke van belang (ROIs) geïdentifiseer in die beskikbare brein beeld data. Lineêre regressie is gebruik om assosiasieanalises te doen om die rolle van ROIs in behandelingsrespons, kindertyd trauma in antipsigotiese reaksies/breinstruktuur te ondersoek, genetiese beeldvorming in antipsigotiese reaksies te ondersoek, en geen-omgewing interaksies in antipsigotiese respons te beeld. Tien genetiese variante in CACNA1C, NRG1 en OXTR het betekenisvolle assosiasie met antipsigotiese respons, na regstelling vir veelvoudige toetsing; ⍺=6.720×10-5 (toevoegingsmodel), ⍺=9.470×10-5 (genotipiese model). Vier-en-dertig betekenisvolle assosiasies met antipsigotiese respons is geïdentifiseer vir GxE met kindertyd trauma en variëteite in CACNA1C, COMT, DISC1, DRD3, NRG1 en OXTR; ⍺=1.120×10-5 (aanvullende model), ⍺=1.578×10-5 (genotipiese model). Nie een van die oorblywende assosiasie-ontledings het beduidende resultate opgelewer nie, en 'n onaangepaste drempel (⍺=0,05) is oorweeg vir die ondersoekende waarneming van genetiese beeldvorming en interaksie-neigings in gene-omgewing interaksie. Vyf GxE wat aansienlik geassosieer is met 'n verbeterde reaksie op antipsigotiese middels, toon tentatiewe neigings vir verhoogde putamen en hippocampus volumes. Aan die ander kant het ses GxE wat aansienlik geassosieer is met 'n swakker behandelingsrespons, neigings getoon vir verminderde volumes van die caudaat, korteks, pallidum, putamen, subkortikale grysstof en totale grysstof. Hierdie bevindings het 'n positiewe korrelasie op tendensvlak uitgelig tussen basislyn ROI volumes en behandelingsrespons (d.w.s. groter ROI volumes en verbeterde antipsigotiese respons, en omgekeerd). Die tentatiewe positiewe korrelasie tussen ROI volumes en antipsigotiese respons in die konteks van GxE dui op 'n meganisme waardeur die verhouding tussen breinstruktuur en antipsigotiese respons bemiddel kan word. In die geheel bied die nuwe betekenisvolle assosiasies, en tendense van belang, die nut van geïntegreerde navorsingsbenaderings om die verhoudings tussen onderliggende molekulêre meganismes en heterogene behandelingsrespons fenotipes meer effektief te ontkoppel.

Please refer to this item in SUNScholar by using the following persistent URL: http://hdl.handle.net/10019.1/108305
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