Citations 2
Genomic dimensions deconstruct the clinical heterogeneity of bipolar disorder
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No container title available | June 25, 2025 | Volume: No volume available | Issue: No issue available | Pages: No page available
ABSTRACT Bipolar disorder’s (BD) clinical heterogeneity has an unresolved genetic basis. We meta-analyzed genome-wide association studies (GWAS) of 16 BD subphenotypes in 226,032 individuals from 57 cohorts (38,022 cases); 10 advanced to multivariate and multi-trait analyses. Four factors (compulsive, psychotic, dysregulated, internalizing) explained 82.8% of shared genetic variance. BD1 and BD2 loaded on distinct factors despite a high genetic correlation; 87.0% of common-factor loci were significant in neither subtype. Unipolar mania aligned with psychosis over internalizing, and was distinguishable from BD1, and rapid cycling showed heritable cross-domain liability. We identified 356 risk loci, 158 novel, including the first univariate-GWAS associations for psychosis, unipolar mania, rapid cycling and schizoaffective disorder—and 249 credible genes (89 high-confidence), 12 with approved-drug or clinical-phase annotations. Cell-type association showed a midbrain dopaminergic–GABAergic gradient along the psychotic factor. BD’s genetic architecture appears hierarchical—a general liability resolving into dimensions of course and comorbidity beyond diagnostic subtypes.
GBA mutations in Parkinson disease: earlier death but similar neuropathological features
Adler, Charles H. , Beach, Thomas G. , Shill, H. A., Caviness, John N., Driver‐Dunckley, Erika, Patel, Amit , Sue, Lucia I., Jacobson, Sandra A. , Davis, Kathryn, Belden, Christine M. , Dugger, Brittany N. , Paciga, Sara A. , Winslow, Ashley R. , Hentz, Joseph G. , Adler, C H , Paciga, S A , Shill, Holly A. , Driver‐Dunckley, Erika , Sabbagh, Marwan Noel , Patel, A., Serrano, Geidy E. , Hirst, Warren D. , Dugger, Brittany N
European Journal of Neurology | August 18, 2017 | Volume: 24 | Issue: 11 | Pages: 1363-1368
Background and purpose Mutations in the glucocerebrosidase ( GBA ) gene are known to be a risk factor for Parkinson's disease ( PD ). Data on clinicopathological correlation are limited. The purpose of this study was to determine the clinicopathological findings that might distinguish PD cases with and without mutations in the GBA gene. Methods Data from the Arizona Study of Aging and Neurodegenerative Disorders were used to identify autopsied PD cases that did or did not have a GBA gene mutation. Clinical and neuropathological data were compared. Results Twelve PD cases had a GBA mutation and 102 did not. The GBA mutation cases died younger (76 vs. 81 years of age) but there was no difference in disease duration or clinical examination findings. No neuropathological differences were found in total or regional semi‐quantitative scores for Lewy‐type synucleinopathy, senile plaques, neurofibrillary tangles, white matter rarefaction or cerebral amyloid angiopathy scores. Conclusions In longitudinally assessed, autopsied PD cases, those with GBA mutations had a younger age at death but there was no evidence for clinical or neuropathological differences compared to cases without GBA mutations. Due to the small GBA group size, small differences cannot be excluded.