Abstract
Although abnormal cortical gyrification has been consistently reported in patients with schizophrenia, whether gyrification abnormalities reflect a genetic risk for the disorder remains unknown. This study investigated differences in cortical gyrification between unaffected relatives (URs) with high genetic loading for schizophrenia and healthy controls (HCs) to identify potential genetic vulnerability markers. A total of 50 URs of schizophrenia patients and 50 matched HCs underwent T1-weighted magnetic resonance imaging to compare whole-brain gyrification using the local gyrification index (lGI). Then, the lGI clusters showing significant differences were compared between the UR subgroups based on the number of first-degree relatives with schizophrenia to identify the effect of genetic loading on cortical gyrification changes. The URs exhibited significantly lower cortical gyrification than the HCs in clusters including medial parieto-occipital and cingulate regions comprising the bilateral precuneus, cuneus, pericalcarine, lingual, isthmus cingulate, and posterior cingulate gyri. Moreover, URs who had two or more first-degree relatives with schizophrenia showed greater gyrification reductions in these clusters than those who had at least one first-degree relative with schizophrenia. Our findings of reduced gyrification in URs, which are consistent with accumulated evidence of hypogyria observed in regions showing patient-control differences in previous studies, highlight that such hypogyria in posteromedial regions may serve as a genetic vulnerability marker and reflect early neurodevelopmental abnormalities resulting from a genetic risk for schizophrenia.
Highlights
Schizophrenia is highly heritable in that biological relatives of patients have an increased risk of developing the disease, and genetic factors constitute significant risk factors in schizophrenia[1]
The unaffected relatives (URs) were divided into the following two groups based on the number of affected first-degree relatives as described in previous studies[27,28]: (1) the “multiplex” group included URs who had at least two firstdegree relatives or monozygotic twins with schizophrenia (n = 9) and (2) the “simplex” group included URs who had only one firstdegree relative with schizophrenia and at least one other affected second- to third-degree relative (n = 41)
No significant group differences were found between the multiplex and simplex UR subgroups except for the sex ratio (Z = 5.767; p = 0.025)
Summary
Schizophrenia is highly heritable in that biological relatives of patients have an increased risk of developing the disease, and genetic factors constitute significant risk factors in schizophrenia[1]. Abnormalities in gyrification, the developmental process of forming cortical sulcal and gyral patterns, have been proposed as a candidate structural endophenotype for schizophrenia[3], and this hypothesis has been supported by its characteristics of high heritability[4] and consistent observations in schizophrenia patients[5,6,7,8,9]. Given that the formation of cortical folding is largely determined during early neurodevelopment and strongly influenced by genetic factors[12,13,14], investigating gyrification changes in URs may help identify a genetic vulnerability marker reflecting the early neurodevelopmental etiopathology of schizophrenia
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