Genetic Overlap Between Alzheimer's Disease and Psychiatric Disorders: Specifying the Shared Genetic Determinants and Causality Between Alzheimer's Disease, Major Depressive Disorder, Bipolar Disorder, and Schizophrenia

Fernandes, Brisa Simões; Enduru, Nitesh; Dai, Yanjun; Zhao, Zhongming

doi:10.1016/j.euroneuro.2022.07.458

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“…While phenotypic overlap of AD and BD with IR-related conditions has been reported frequently (e.g., Santiago and Potashkin (2021); Wimberley et al (2022)), previous genetic analyses did not find global genetic correlations between these phenotypes (Fanelli et al, 2022a), potentially due to the averaging effect of global analyses. Our study, which is the first to report significant local genetic correlations between AD, BD, TS and IR-related conditions, suggests that positive and negative local correlations may regularly neutralise each other in global correlation analyses, a phenomenon observed in other recent studies (Arenella et al, 2023;Fernandes et al, 2023), and should be taken into account for future research. These heterogeneous patterns of genetic overlap could point towards aetiologically distinct subgroups, which could be examined in greater detail using deep phenotyping and functional validation.…”

Section: Discussionsupporting

confidence: 70%

Local patterns of genetic sharing challenge the boundaries between neuropsychiatric and insulin resistance-related conditions

Fanelli,

Franke,

Fabbri

et al. 2024

Preprint

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The co-occurrence of insulin resistance (IR)-related metabolic conditions with neuropsychiatric disorders is a complex public health challenge. Evidence of the genetic links between these phenotypes is emerging, but little is currently known about the genomic regions and biological functions that are involved. To address this, we performed Local Analysis of [co]Variant Association (LAVA) using large-scale (N=9,725-933,970) genome-wide association studies (GWASs) results for three IR-related conditions (type 2 diabetes mellitus, obesity, and metabolic syndrome) and nine neuropsychiatric disorders. Subsequently, positional and expression quantitative trait locus (eQTL)-based gene mapping and downstream functional genomic analyses were performed on the significant loci. Patterns of negative and positive local genetic correlations (|rg|=0.21-1, pFDR<0.05) were identified at 109 unique genomic regions across all phenotype pairs. Local correlations emerged even in the absence of global genetic correlations between IR-related conditions and Alzheimer's disease, bipolar disorder, and Tourette's syndrome. Genes mapped to the correlated regions showed enrichment in biological pathways integral to immune-inflammatory function, vesicle trafficking, insulin signalling, oxygen transport, and lipid metabolism. Colocalisation analyses further prioritised 10 genetically correlated regions for likely harbouring shared causal variants, displaying high deleterious or regulatory potential. These variants were found within or in close proximity to genes, such asSLC39A8andHLA-DRB1, that can be targeted by supplements and already known drugs, including omega-3/6 fatty acids, immunomodulatory, antihypertensive, and cholesterol-lowering drugs. Overall, our findings underscore the complex genetic landscape of IR-neuropsychiatric multimorbidity, advocating for an integrated disease model and offering novel insights for research and treatment strategies in this domain.

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Section: Discussionsupporting

confidence: 70%