medwireNews: Rare copy-number variants (CNVs) that confer a high risk for schizophrenia or autism are associated with impaired cognition in carriers without psychiatric disorders, researchers report in Nature.
“One of the missing pieces in our understanding of the pathogenesis of schizophrenia has been the nature of the physiologic function that is first perturbed in the disease or the perturbation of which leads to the disease,” say study author Kari Stefansson (deCODE genetics/Amgen, Reykjavík, Iceland) and team.
They add: “We suggest that the work presented here lends support to the idea that the cognitive abnormalities are fundamental defects in schizophrenia as they are manifest in carriers of CNVs conferring risk of the disease who do not suffer from the disease.”
The 26 CNV alleles studied were rare, occurring in just 1.16% of 101,655 genotyped Icelandic people. From among these participants, the team identified 167 who carried neuropsychiatric CNVs but had not been diagnosed with a psychiatric condition.
When administered a battery of neurocognitive tests, these people had significantly poorer performance than 475 controls without CNVs, although they scored significantly better than 161 patients with schizophrenia. The performance of a further 465 people carrying CNVs not previously linked to psychiatric disorders was in line with that of controls.
Eleven neuropsychiatric CNVs occurred in at least five carriers who did not have a mental disorder, and eight of these had direct associations with neurocognition, with six having a large effect size (0.73–3.51 standard deviations below controls).
For example, the 16p11.2 deletion conferred impaired verbal IQ and poor performance in verbal letter and category fluency tests, as seen in patients with autism, but its duplication was associated with impaired spatial working memory and other executive functions known to be affected in schizophrenia.
The associations were much weaker after accounting for IQ, which the researchers say “is not surprising as the cognitive tests measure attributes that contribute to IQ.”
The 15q11.2(BP1-BP2) deletion had only modest effects on neurocognition, yet it was strongly associated with a history of difficulty in learning reading and mathematics, and with probable dyslexia and dyscalculia.
In line with findings in schizophrenia patients, 15 carriers of this deletion who underwent magnetic resonance imaging had reduced gray matter volume in the perigenual anterior cingulate cortex and the left insula, and in white matter in the temporal lobe bilaterally. However, they had an increased volume of the corpus callosum, contrary to the reductions seen in patients.
Importantly, reciprocal effects were seen in 15q11.2(BP1-BP2) duplication carriers, “providing the first demonstration of allele-dose-dependent effects of CNVs on the structure of the human brain,” says the team.
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By Eleanor McDermid, Senior medwireNews Reporter