Genetic and neuropsychological studies have each made important contributions to the understanding of schizophrenia. Family, twin and adoption studies provide strong support for a genetic component in the etiology and schizophrenia, and neurodiagnostic approaches strongly indicate the presence of brain dysfunction in many schizophrenics. Moreover, variability in the occurrence of mental illness in the relatives of schizophrenics and variability in the types and severity of structural, physiological and functional abnormalities suggests significant genetic and neuropsychological heterogeneity within schizophrenia. Linking these two research domains thus represents a crucial step toward elucidating the heterogeneity of schizophrenia. This proposal is for a unified investigation of genetic and neuropsychological heterogeneity in schizophrenia with the goal of determining whether specific types of neuropsychological deficits reflect familial or nonfamilial etiological factors. Using the family study method, the proposed research plan is to diagnose psychiatric hospital patients and normal controls, and their first degree relatives using structured psychiatric interviews, and to assess all of these individuals with a comprehensive neuropsychological battery. Genetic heterogeneity will be assessed by dividing schizophrenics into familial and nonfamilial subgroups defined on the basis of the family study. Specificity of neuropsychological deficits to familial and nonfamilial schizophrenia will be assessed by comparing the schizophrenic subgroups to bipolar and normal control groups. The study will compare the ability of seven different models of schizophrenia to account for the patterns of neuropsychological variability among the schizophrenic groups and their relatives. The results will also be used to determine the heritability of neuropsychological deficits, to determine which measures may be vulnerability markers for schizophrenia, and to study neuropsychological impairment as an alternative schizophrenic phenotype for use in segregation analyses. By elucidating the genetic and neuropsychological heterogeneity of schizophrenia, the proposed study will clarify underlying mechanisms and aid in the development of homogeneous subgroups that will be informative for future etiological and pathophysiological research. The delineation of neuropsychological profiles and familial and nonfamilial forms of schizophrenia will contribute to psychiatric genetic counseling and to the development of treatment-relevant subgroups.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Method to Extend Research in Time (MERIT) Award (R37)
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Psychopathology and Clinical Biology Research Review Committee (PCB)
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Harvard University
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Brent, Benjamin K; Rosso, Isabelle M; Thermenos, Heidi W et al. (2016) Alterations of lateral temporal cortical gray matter and facial memory as vulnerability indicators for schizophrenia: An MRI study in youth at familial high-risk for schizophrenia. Schizophr Res 170:123-9
Manschreck, T C; Chun, J; Merrill, A M et al. (2015) Impaired motor performance in adolescents at familial high-risk for schizophrenia. Schizophr Res 168:44-9
Auther, A M; Cadenhead, K S; CarriĆ³n, R E et al. (2015) Alcohol confounds relationship between cannabis misuse and psychosis conversion in a high-risk sample. Acta Psychiatr Scand 132:60-8
Seidman, Larry J; Hellemann, Gerhard; Nuechterlein, Keith H et al. (2015) Factor structure and heritability of endophenotypes in schizophrenia: findings from the Consortium on the Genetics of Schizophrenia (COGS-1). Schizophr Res 163:73-9
Seidman, Larry J; Rosso, Isabelle M; Thermenos, Heidi W et al. (2014) Medial temporal lobe default mode functioning and hippocampal structure as vulnerability indicators for schizophrenia: a MRI study of non-psychotic adolescent first-degree relatives. Schizophr Res 159:426-34
Walder, Deborah J; Faraone, Stephen V; Glatt, Stephen J et al. (2014) Genetic liability, prenatal health, stress and family environment: risk factors in the Harvard Adolescent Family High Risk for schizophrenia study. Schizophr Res 157:142-8
Light, Gregory; Greenwood, Tiffany A; Swerdlow, Neal R et al. (2014) Comparison of the heritability of schizophrenia and endophenotypes in the COGS-1 family study. Schizophr Bull 40:1404-11
Scala, Silvia; Pousada, Andrea; Stone, William S et al. (2013) Verbal and visual-spatial memory impairment in youth at familial risk for schizophrenia or affective psychosis: a pilot study. Schizophr Res 144:122-8
Da Silva, Felipe N; Irani, Farzin; Richard, Jan et al. (2012) More than just tapping: index finger-tapping measures procedural learning in schizophrenia. Schizophr Res 137:234-40
Seidman, Larry J; Meyer, Eric C; Giuliano, Anthony J et al. (2012) Auditory working memory impairments in individuals at familial high risk for schizophrenia. Neuropsychology 26:288-303

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