The
neurotransmitter disturbances responsible for
cognitive dysfunction in
schizophrenia are hypothesized to originate with alterations in postsynaptic scaffold
proteins. We have recently reported that
protein levels of FRMPD4, a multiscaffolding
protein that modulates both Homer1 and
postsynaptic density protein 95 activity, is altered in the
schizophrenia postmortem brain, in regions involved in cognition. Here, we set out to investigate whether genetic variation in FRMPD4 is associated with cognitive function in people with
schizophrenia. We selected and examined a novel single nucleotide polymorphism, rs5979717 (positioned in the noncoding
3' untranslated region of FRMPD4 and potentially influencing
protein expression), for its association with
schizophrenia and nine measures of cognitive function, using age-matched and sex-matched samples from 268
schizophrenia cases and 268 healthy controls. Brain samples from 20
schizophrenia patients and 20 healthy controls were additionally genotyped to study the influence of this variant on
protein expression of FRMPD4. Allelic distribution of rs5979717 was associated with
schizophrenia in females (χ=4.52, P=0.030). No effects of rs5979717 were observed on cognitive performance, nor an influence of rs5979717 genotypes on the expression of FRMPD4
proteins in postmortem brain samples. These data provide initial support for a sex-specific role for common variation in rs5979717 in
schizophrenia, which now warrants further investigation.