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Genetic Associations Between Schizophrenia & Neuregulin-1: A Strategy of Convergent Validity with Cognition

Yokley, Jessica Lauren (2009) Genetic Associations Between Schizophrenia & Neuregulin-1: A Strategy of Convergent Validity with Cognition. Master's Thesis, University of Pittsburgh. (Unpublished)

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Recent work shows potentially promising associations between schizophrenia and polymorphisms in Neuregulin-1 (NRG1). A large literature has also found strong familial relationships between schizophrenia and cognitive deficits. Given the role of NRG1 in glutamate-NMDAR regulation, we hypothesize that cognitive deficits may be related to sequence variation within NRG1, thus providing a possible mechanism by which NRG1 could act as a susceptibility gene for schizophrenia. This study examined the associations between NRG1, cognition, and schizophrenia using a multigenerational multiplex family sample (419 individuals from 40 families), including 58 affected participants (schizophrenia or schizoaffective disorder, depressed type) and their 361 unaffected relatives. In total, three samples were created from this participant pool: 1) the total sample, including affected and unaffected participants; 2) an unaffected subsample, consisting of only unaffected participants; and 3) the ¡°No Diagnosis¡± subsample, consisting of participants with no diagnosis on the DIGS. In addition, a control group (N=199) was included for standardization of the cognitive data, but was not genotyped. Pedigree participants were genotyped using the SNPlex procedure for 40 NRG1 single nucleotide polymorphisms (SNPs). All participants completed structured diagnostic interviews and were administered a previously validated computerized neurocognitive battery that assessed eight cognitive domains, including: abstraction/mental flexibility, attention, verbal/facial/spatial memory, spatial/emotional processing, and sensorimotor dexterity. Pedigree-based variance component quantitative trait analyses using SOLAR were performed to test for associations between individual NRG1 SNPs and cognitive performance. Although the specific associations that were significant differed somewhat among subsamples, each sample had between 14-25 significant (p¡Ü0.05) associations, encompassing multiple SNPs and multiple cognitive domains. The numerous significant findings in progressively diagnostically ¡°cleaner¡± sub-samples may suggest that variation in NRG1 is more directly associated with cognition and is not solely secondary to an effect of schizophrenia or psychopathology. These associations may suggest a role for NRG1 in cognition that is a mediating risk factor for schizophrenia and/or psychopathology more generally. It is also possible that these associations with cognition are irrelevant to schizophrenia, but the literature on NRG1 and schizophrenia argues against this possibility.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Yokley, Jessica Laurenjly14@pitt.eduJLY14
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairPogue-Geile, MFmfpg@pitt.eduMFPG
Committee MemberPrasad, Kprasadkm@upmc.eduKMP8
Committee MemberAlmasy,
Committee MemberNimgaonkar,
Date: 30 September 2009
Date Type: Completion
Defense Date: 17 April 2009
Approval Date: 30 September 2009
Submission Date: 11 May 2009
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Institution: University of Pittsburgh
Schools and Programs: Dietrich School of Arts and Sciences > Psychology
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: Neuregulin-1; NRG1; Schizophrenia
Other ID:, etd-05112009-145810
Date Deposited: 10 Nov 2011 19:44
Last Modified: 19 Dec 2016 14:36


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