Publications by authors named "E M Scolnick"

Despite tremendous effort, the molecular and cellular basis of cognitive deficits in schizophrenia remain poorly understood. Recent progress in elucidating the genetic architecture of schizophrenia has highlighted the association of multiple loci and rare variants that may impact susceptibility. One key example, given their potential etiopathogenic and therapeutic relevance, is a set of genes that encode proteins that regulate excitatory glutamatergic synapses in brain.

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Article Synopsis
  • A meta-analysis of whole exomes from 24,248 schizophrenia cases and 97,322 controls identified ultra-rare coding variants (URVs) linked to schizophrenia risk across 10 significant genes.
  • Some of these genes are heavily expressed in the brain and are involved in synapse formation, pointing to a connection between glutamate system dysfunction and schizophrenia.
  • Additionally, there's an overlap in rare variant risks shared with other disorders like autism and epilepsy, suggesting that both common and rare genetic factors contribute to the same biological processes underlying schizophrenia.
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A missense mutation (A391T) in SLC39A8 is strongly associated with schizophrenia in genomic studies, though the molecular connection to the brain is unknown. Human carriers of A391T have reduced serum manganese, altered plasma glycosylation, and brain MRI changes consistent with altered metal transport. Here, using a knock-in mouse model homozygous for A391T, we show that the schizophrenia-associated variant changes protein glycosylation in the brain.

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Schizophrenia (SCZ) is a chronic, serious mental disorder. Although more than 200 SCZ-associated genes have been identified, the underlying molecular and cellular mechanisms remain largely unknown. Here, we generated a Setd1a (SET domain containing 1A) haploinsufficiency mouse model to understand how this SCZ-associated epigenetic factor affects gene expression in brain regions highly relevant to SCZ.

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