Abstract
Schizophrenia is a highly heritable disorder for which anatomical brain alterations have been repeatedly reported in clinical samples. Unaffected at-risk groups have also been studied in an attempt to identify brain changes that do not reflect reverse causation or treatment effects. However, no robust associations have been observed between neuroanatomical phenotypes and known genetic risk factors for schizophrenia. We tested subcortical brain volume differences between 49 unaffected participants carrying at least one of the 12 copy number variants associated with schizophrenia in UK Biobank and 9063 individuals who did not carry any of the 93 copy number variants reported to be pathogenic. Our results show that CNV carriers have reduced volume in some of the subcortical structures previously shown to be reduced in schizophrenia. Moreover, these associations partially accounted for the association between pathogenic copy number variants and cognitive impairment, which is one of the features of schizophrenia.
Highlights
Schizophrenia (SZ) is a severe psychiatric disorder with a profound impact on affected individuals, their families and society
Since cognitive impairment is a core feature of SZ and previous research has shown genetic overlap between IQ and SZ [17], we aimed to examine whether a previously reported association between SZ-copy number variation (CNV) and cognitive performance [18] was mediated by subcortical volume alterations
The main aim of this study was to ascertain whether unaffected SZ-associated CNVs (SZ-CNVs) carriers present similar anatomical alterations in subcortical volumes to those previously found in clinical samples
Summary
Schizophrenia (SZ) is a severe psychiatric disorder with a profound impact on affected individuals, their families and society. Patients with SZ have an average life expectancy 10–20 years shorter than the general population, around 20% experience chronic psychotic symptoms, 50% long-term psychiatric problems and 80–90% unemployment [1,2,3,4]. Our ability to treat SZ remains limited and no new therapeutic targets of proven efficacy have been developed for decades. Clozapine, discovered almost six decades ago, still stands as the most effective treatment for SZ [5]. This lack of progress is due to our poor understanding of the neurobiological underpinnings of the disorder; recent developments in brain imaging have opened new opportunities to advance on this knowledge
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