Effects of GRASP variation on memory in psychiatrically healthy individuals and cognitive dysfunction in schizophrenics

Mechanistic studies indicate general receptor for phosphoinositides-1-associated scaffold protein (GRASP, also referred to as Tamalin) is involved in neurite development, proliferation, and branching in hippocampal neurons, but its physiological effects on cognitive function is mostly unknown. Cognitive impairment is a core feature of schizophrenia, and recent reports indicate increased abundance of GRASP proteins in postmortem schizophrenia cortex and hippocampus, both of these structures being highly relevant to cognitive processes. We therefore assessed the effects of a single nucleotide polymorphism (SNP) rs10876227 [G > A] in GRASP on eight different domains of cognitive function in a well-established Caucasian case-control cohort for schizophrenia. In 261 control individuals (166 males), strong effects of rs10876227 were observed on immediate memory, delayed memory, and working memory, with the major G allele associated with worse memory performance on each test. Additional analyses including 249 patients with schizophrenia (174 males) indicated that the G allele of rs10876227 was also able to distinguish male schizophrenia participants with severe cognitive deficits (CD; 81 males) from male schizophrenia participants with relatively spared cognitive function (CS; 91 males). However analyses of the effects of GRASP variation on individual cognitive domains in the combined sample showed no interactive effects of clinical status and rs10876227 variation. These findings converge with prior mechanistic and postmortem studies to strongly support contribution of GRASP variation to memory function, and general cognitive ability in men with schizophrenia, likely via GRASP-directed plasticity. The implications of these findings extend to other disorders where cognitive function is a core component, such as dementia, autism and mental retardation.