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Developmental Neurogenetics of Cortical Thickness and Cortical Surface Area in Schizophrenia: A Multiplex Extended Pedigree Study

Kuo, Szu-Yu Susan (2020) Developmental Neurogenetics of Cortical Thickness and Cortical Surface Area in Schizophrenia: A Multiplex Extended Pedigree Study. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Peak age of onset for schizophrenia occurs during late adolescence and early adulthood, a critical period for brain development (Häfner, 2003). Schizophrenia genetic effects on neurodevelopment may remain stable from childhood (as proposed by early neurodevelopmental models), increase during adulthood closer to the peak age-of-onset (late neurodevelopmental models) (Pogue-Geile, 1991), or increase long after the peak age-of-onset (neurodegenerative models) (Lieberman, 1999). To our knowledge, no study to date has directly tested these developmental neurogenetic effects. To address this question, 230 participants (age range: 12-85 years) from 32 multigenerational families with at least two first-degree schizophrenia relatives and 276 unrelated controls underwent diagnostic interview and magnetic resonance imaging (MRI). Participants were stratified into age-risk periods based on their ages relative to population incidences of schizophrenia onset at the peak (22 years) and plateau (42 years): rising effects (younger than 23 years), peak effects (23-42 years), and plateau effects (older than 42 years). Quantitative imaging genetic analyses were conducted using SOLAR-Eclipse maximum-likelihood genetic variance decomposition algorithms on FreeSurfer MRI parcellations of bilateral cortical thickness and surface area. The effects of schizophrenia genetic risk were found to influence different aspects of brain structure before and after schizophrenia peak age-of-onset: early schizophrenia genetic effects influenced frontal and cingulate surface area, whereas late schizophrenia genetic effects are more widespread and influence both regional thickness (across frontal, parietal, temporal, and cingulate regions) and regional surface area (across parietal, temporal, and cingulate regions). Furthermore, neurodegenerative schizophrenia genetic effects particularly influenced frontal and temporal thickness. This pattern was diagnostically specific to schizophrenia and not found in depression. Our findings bear important implications for multiple levels of systems genetic investigations: targets of genome-wide searches for schizophrenia genetic risk variants may be refined by examining specific cortical regions depending on the participants’ ages relative to schizophrenia peak age-of-onset and changes in the expression of schizophrenia genetic risk variants across neurodevelopment of specific cortical regions may provide mechanistic insights into the development of schizophrenia. Overall, our findings emphasize the utility of using developmental approaches to inform genetic investigations of schizophrenia.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Kuo, Szu-Yu Susansusan.kuo@pitt.edusuk82
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairPogue-Geile,
Committee MemberShaw,
Committee MemberHanson,
Committee MemberPrasad,
Committee MemberLuna,
Committee MemberJalbrzikowski,
Date: 16 September 2020
Date Type: Publication
Defense Date: 26 September 2019
Approval Date: 16 September 2020
Submission Date: 19 February 2020
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 238
Institution: University of Pittsburgh
Schools and Programs: Dietrich School of Arts and Sciences > Psychology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: imaging genetics, neurodevelopment, brain structure, brain morphology, genetic correlation, age of onset, prodrome, genetic high risk, familial high risk
Date Deposited: 16 Sep 2020 14:21
Last Modified: 16 Sep 2022 05:15


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