Shared genetics of psychiatric disorders and type 2 diabetes:a large-scale genome-wide cross-trait analysis

Ding, Hui; Ouyang, Mengyuan; Wang, Jinyi; Xie, Minyao; Huang, Yanyuan; Yuan, Fangzheng; Jia, Yunhan; Zhang, Xuedi; Liu, Na; Zhang, Ning

doi:10.1016/j.jpsychires.2023.01.037

Cited by 12 publications

(5 citation statements)

References 79 publications

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“…They found that high polygenic risk scores for schizophrenia were associated with decreased cardiac volumes and increased ejection fractions, suggesting a genetic overlap between schizophrenia and some at-risk cardiac phenotypes. It is known that persons with schizophrenia are vulnerable to Type 2 diabetes not only because antipsychotic drugs can induce diabetes [ 28 ], but also because there are genetic overlaps between diabetes and schizophrenia [ 29 , 30 ]. Importantly, diabetes is a risk factor for cardiac disease [ 31 ].…”

Section: Resultsmentioning

confidence: 99%

Monitoring the Effectiveness of Treatment in Women with Schizophrenia: New Specialized Cooperative Approaches

Natividad,

Seeman,

Paolini

et al. 2023

Brain Sciences

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Women with schizophrenia have specific health needs that differ from those of men and that change through successive life stages. We aimed to review the biopsychosocial literature on schizophrenia that addresses clinically important questions related to the treatment of women, including somatic morbi-mortality, hyperprolactinemia, comorbid substance use disorders, social risk factors, and medication effectiveness/safety. Data search terms were as follows: (Morbidity AND mortality) OR hyperprolactinemia OR (“substance use disorders” OR addictions) OR (“social risk factors”) OR (“drug safety” OR prescription) AND women AND schizophrenia. A secondary aim was to describe a method of monitoring and interdisciplinary staff strategies. Schizophrenia patients show an increased risk of premature death from cardiovascular/respiratory disease and cancer compared to the general population. The literature suggests that close liaisons with primary care and the introduction of physical exercise groups reduce comorbidity. Various strategies for lowering prolactin levels diminish the negative long-term effects of hyperprolactinemia. Abstinence programs reduce the risk of victimization and trauma in women. Stigma associated with women who have serious psychiatric illness is often linked to reproductive functions. The safety and effectiveness of antipsychotic drug choice and dose differ between men and women and change over a woman’s life cycle. Monitoring needs to be multidisciplinary, knowledgeable, and regular.

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Section: Resultsmentioning

confidence: 99%

Monitoring the Effectiveness of Treatment in Women with Schizophrenia: New Specialized Cooperative Approaches

Natividad,

Seeman,

Paolini

et al. 2023

Brain Sciences

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“…If these previous region-level findings for AKT protein expression extend to neurons, the increases in neuronal AKT1-3 mRNAs found in the present study support a hypothesis of pathological uncoupling of AKT transcript and protein expression. Given the perturbation of insulin signaling in schizophrenia [55,68,69], neurons may be transcribing more mRNA in an attempt to compensate for decreased AKT activity and/or downstream effects of lower AKT signaling including diminished glucose utilization [70,71].…”

Section: Discussionmentioning

confidence: 99%

Neuronal alterations in AKT isotype expression in schizophrenia

McCullumsmith,

Imami,

Eby

et al. 2024

Preprint

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Schizophrenia is characterized by substantial alterations in brain function, and previous studies suggest insulin signaling pathways, particularly involving AKT, are implicated in the pathophysiology of the disorder. This study demonstrates elevated mRNA expression of AKT1-3 in neurons from schizophrenia subjects, contrary to unchanged or diminished total AKT protein expression reported in previous postmortem studies, suggesting a potential decoupling of transcript and protein levels. Sex-specific differential AKT activity was observed, indicating divergent roles in males and females with schizophrenia. Alongside AKT, upregulation of PDPK1, a critical component of the insulin signaling pathway, and several protein phosphatases known to regulate AKT were detected. Moreover, enhanced expression of the transcription factor FOXO1, a regulator of glucose metabolism, hints at possible compensatory mechanisms related to insulin signaling dysregulation. Findings were largely independent of antipsychotic medication use, suggesting inherent alterations in schizophrenia. These results highlight the significance of AKT and related signaling pathways in schizophrenia, proposing that these changes might represent a compensatory response to a primary defect of conical insulin signaling pathways. This research underscores the need for a detailed understanding of these signaling pathways for the development of effective therapeutic strategies.

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“…There are multiple risk factors which may contribute to the link between schizophrenia and T2D. It has been documented that genetic predisposition and loci are shared by the two disorders [2,[16][17][18]. In addition, prediabetes and T2D may develop as side effects of certain psychotic agents.…”

Section: Insulin Resistance/prediabetes and Diabetes Are Highly Preva...mentioning

confidence: 99%

“…A growing body of evidence obtained from large-scale across-trait GWAS supports a shared genetic basis for comorbidity of schizophrenia and T2D. Most recently, Ding et al investigated potential shared genetic overlap between T2D and psychiatric disorders, including schizophrenia, by conducting a large-scale across-trait GWAS [16]. A protein-protein interaction (PPI) analysis identified transcription factor 7-like 2 (TCF7L2) and fat mass and obesity-associated (FTO) protein, also known as alphaketoglutarate-dependent dioxygenase.…”

Section: Evidence From Observational Studies In Humans and Other Clin...mentioning

confidence: 99%

“…A protein-protein interaction (PPI) analysis identified transcription factor 7-like 2 (TCF7L2) and fat mass and obesity-associated (FTO) protein, also known as alphaketoglutarate-dependent dioxygenase. The genes encoding these two proteins (TCF7L2 and FTO) play key roles in the differentially expressed gene (DEG)-based PPI network [16] and are well-known T2D susceptibility genes. An association of a TCF7L2 variant with T2D risk was first reported in 2006 [44].…”

Section: Evidence From Observational Studies In Humans and Other Clin...mentioning

confidence: 99%

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Insulin Resistance/Diabetes and Schizophrenia: Potential Shared Genetic Factors and Implications for Better Management of Patients with Schizophrenia

Zhuo,

Zhang,

Wang

et al. 2023

CNS Drugs

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Schizophrenia is a complex psychotic disorder with co-occurring conditions, including insulin resistance and type 2 diabetes (T2D). It is well established that T2D and its precursors (i.e., insulin resistance) are more prevalent in patients with schizophrenia who are treated with antipsychotics, as well as in antipsychotic-naïve patients experiencing their first episode of psychosis, compared with the general population. However, the mechanism(s) underlying the increased susceptibility, shared genetics, and possible cause-effect relationship between schizophrenia and T2D remain largely unknown. The objective of this narrative review was to synthesize important studies, including Mendelian randomization (MR) analyses that have integrated genome-wide association studies (GWAS), as well as results from in vitro models, in vivo models, and observational studies of patients with schizophrenia. Both GWAS and MR studies have found that schizophrenia and T2D/insulin resistance share genetic risk factors, and this may mediate a connection between peripheral or brain insulin resistance and T2D with cognition impairment and an increased risk of developing prediabetes and T2D in schizophrenia. Moreover, accumulating evidence supports a causal role for insulin resistance in schizophrenia and emphasizes the importance of a genetic basis for susceptibility to T2D in patients with schizophrenia before they receive psychotic treatment. The present findings and observations may have clinical implications for the development of better strategies to treat patients with schizophrenia, with both pharmacological (i.e., samidorphan, empagliflozin) and/or nonpharmacological (i.e., lifestyle changes) approaches. Additionally, this review may benefit the design of future studies by physicians and clinical investigators.

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Shared genetics of psychiatric disorders and type 2 diabetes:a large-scale genome-wide cross-trait analysis

Cited by 12 publications

References 79 publications

Monitoring the Effectiveness of Treatment in Women with Schizophrenia: New Specialized Cooperative Approaches

Monitoring the Effectiveness of Treatment in Women with Schizophrenia: New Specialized Cooperative Approaches

Neuronal alterations in AKT isotype expression in schizophrenia

Insulin Resistance/Diabetes and Schizophrenia: Potential Shared Genetic Factors and Implications for Better Management of Patients with Schizophrenia

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