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Polygenic risk score for schizophrenia and structural brain connectivity in older age: A longitudinal connectome and tractography study.

ABSTRACT: Higher polygenic risk score for schizophrenia (szPGRS) has been associated with lower cognitive function and might be a predictor of decline in brain structure in apparently healthy populations. Age-related declines in structural brain connectivity-measured using white matter diffusion MRI -are evident from cross-sectional data. Yet, it remains unclear how graph theoretical metrics of the structural connectome change over time, and whether szPGRS is associated with differences in ageing-related changes in human brain connectivity. Here, we studied a large, relatively healthy, same-year-of-birth, older age cohort over a period of 3 years (age???73 years, N?=?731; age ?76 years, N?=?488). From their brain scans we derived tract-averaged fractional anisotropy (FA) and mean diffusivity (MD), and network topology properties. We investigated the cross-sectional and longitudinal associations between these structural brain variables and szPGRS. Higher szPGRS showed significant associations with longitudinal increases in MD in the splenium (??=?0.132, p_FDR?=?0.040), arcuate (??=?0.291, p_FDR?=?0.040), anterior thalamic radiations (??=?0.215, p_FDR?=?0.040) and cingulum (??=?0.165, p_FDR?=?0.040). Significant declines over time were observed in graph theory metrics for FA-weighted networks, such as mean edge weight (??=?-0.039, p_FDR?=?0.048) and strength (??=?-0.027, p_FDR?=?0.048). No significant associations were found between szPGRS and graph theory metrics. These results are consistent with the hypothesis that szPGRS confers risk for ageing-related degradation of some aspects of structural connectivity.

SUBMITTER: Alloza C

PROVIDER: S-EPMC6215331 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Polygenic risk score for schizophrenia and structural brain connectivity in older age: A longitudinal connectome and tractography study.

Alloza C C Cox S R SR Blesa Cábez M M Redmond P P Whalley H C HC Ritchie S J SJ Muñoz Maniega S S Valdés Hernández M Del C MDC Tucker-Drob E M EM Lawrie S M SM Wardlaw J M JM Deary I J IJ Bastin M E ME

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Higher polygenic risk score for schizophrenia (szPGRS) has been associated with lower cognitive function and might be a predictor of decline in brain structure in apparently healthy populations. Age-related declines in structural brain connectivity-measured using white matter diffusion MRI -are evident from cross-sectional data. Yet, it remains unclear how graph theoretical metrics of the structural connectome change over time, and whether szPGRS is associated with differences in ageing-related ...[more]

PMID: 30179718

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Project description:The use of polygenic risk scores has become a practical translational approach to investigating the complex genetic architecture of schizophrenia, but the link between polygenic risk scores and pathophysiological components of this disorder has been the subject of limited research. We investigated in healthy volunteers whether schizophrenia polygenic risk score predicts hippocampal activity during simple memory encoding, which has been proposed as a risk-associated intermediate phenotype of schizophrenia. We analysed the relationship between polygenic risk scores and hippocampal activity in a discovery sample of 191 unrelated healthy volunteers from the USA and in two independent replication samples of 76 and 137 healthy unrelated participants from Europe and the USA, respectively. Polygenic risk scores for each individual were calculated as the sum of the imputation probability of reference alleles weighted by the natural log of odds ratio from the recent schizophrenia genome-wide association study. We examined hippocampal activity during simple memory encoding of novel visual stimuli assessed using blood oxygen level-dependent functional MRI. Polygenic risk scores were significantly associated with hippocampal activity in the discovery sample [P = 0.016, family-wise error (FWE) corrected within Anatomical Automatic Labeling (AAL) bilateral hippocampal-parahippocampal mask] and in both replication samples (P = 0.033, FWE corrected within AAL right posterior hippocampal-parahippocampal mask in Bari sample, and P = 0.002 uncorrected in the Duke Neurogenetics Study sample). The relationship between polygenic risk scores and hippocampal activity was consistently negative, i.e. lower hippocampal activity in individuals with higher polygenic risk scores, consistent with previous studies reporting decreased hippocampal-parahippocampal activity during declarative memory tasks in patients with schizophrenia and in their healthy siblings. Polygenic risk scores accounted for more than 8% of variance in hippocampal activity during memory encoding in discovery sample. We conclude that polygenic risk scores derived from the most recent schizophrenia genome-wide association study predict significant variability in hippocampal activity during memory encoding in healthy participants. Our findings validate mnemonic hippocampal activity as a genetic risk associated intermediate phenotype of schizophrenia, indicating that the aggregate neurobiological effect of schizophrenia risk alleles converges on this pattern of neural activity.awy004media15749593779001.

Dataset Information

Polygenic risk score for schizophrenia and structural brain connectivity in older age: A longitudinal connectome and tractography study.

Publications

Polygenic risk score for schizophrenia and structural brain connectivity in older age: A longitudinal connectome and tractography study.

Similar Datasets

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