Evaluating the Causal Association Between Genetically Proxied Psychiatric Disorders and SuperAging

Abstract

AbstractBackgroundSuperAgers are individuals aged 80+ who have episodic memory capacity that would be considered at least average for those 2‐3 decades younger. The causal factors for SuperAging are not known. Observational studies have linked psychiatric disorders with the risk for late life cognitive decline. It is not known if psychiatric disorders or their genetic liability have a causal effect on SuperAging. We sought to assess the causal relationship between genetically proxied psychiatric disorders (major depression (MD), bipolar disorder (BD), and schizophrenia (SCZ)) and SuperAging using a 2‐sample Mendelian randomization (MR). For comparison, we performed secondary analyses for the association of the same exposures with Alzheimer’s dementia (AD), Lewy Body dementia (LBD), and Frontotemporal dementia (FTD).MethodGenome‐wide significant single nucleotide polymorphisms (SNPs) associated with MD (102 SNPs, 246,363 cases, 561,190 controls), BD (64 SNPs, 41,917 cases, 371,549 controls) and SCZ (287 SNPs, 76,755 cases, 243,649 control), were used as genetic proxies for the exposures. Summary statistics of the genome wide association study (GWAS) for SuperAging was included as the primary outcome (69 SuperAgers, 3,479 controls). Summary statistics were obtained for the largest GWAS studies of neurodegenerative disorders: AD (111,326 cases, 677,663 controls), LBD (2,591 cases, 4,027 controls) and FTD (2,154 cases, 4,308 controls). Inverse variance weighted MR was performed as the main analysis for testing the relationship between the exposures and outcomes.ResultMR analyses showed a significant association between higher genetic liability to SCZ and lower likelihood of SuperAging (OR = 0.98, P = 0.02), but no significant association between MD or BD with SuperAging (P>0.05). Secondary analyses showed that genetic liability to BD was associated with an increased risk for AD (OR = 1.1, P = 0.003), while genetic liability to SCZ was associated with an increased risk for FTD (OR = 1.16, P = 0.04).ConclusionThis is the first study to investigate the potentially causal factors for SuperAging. We found that genetic liability to SCZ is causally associated with lower likelihood of SuperAging. We also found that the genetic liability to BP and SCZ are associated with an increased risk for AD and FTD, respectively. Further exploration of causal factors to SuperAging is warranted.