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Genetic Overlap Between Schizophrenia, Cardiovascular Disease Risk Uncovered by GWAS Analysis

NEW YORK – By analyzing several genome-wide association studies (GWAS), researchers from Norway found that people with schizophrenia have a reduced risk of obesity but an increased genetic predisposition to smoking.

While it is known that schizophrenia is associated with a nearly threefold increased risk of cardiovascular disease (CVD), the new findings suggest that environmental and lifestyle factors, more than genetics, lead to this elevated risk, they said.

As reported in the American Journal of Psychiatry on Wednesday, the investigators found an extensive genetic overlap between schizophrenia and CVD risk factors, especially noting that people with schizophrenia genetically tend to have a lower body mass index (BMI).

"Our findings suggest that high obesity rates seen in schizophrenia patients are likely a result of antipsychotic medications, stress, and lifestyle factors after their diagnosis, rather than it being driven by genetics," lead author Linn Rødevand, a researcher with the Norwegian Center for Mental Disorders Research at the University of Oslo, told GenomeWeb.

For this study, her team retrieved GWAS results for schizophrenia from the Psychiatric Genomics Consortium, containing genetic information of 53,386 patients with schizophrenia and 77,258 controls of European descent, along with GWAS data on CVD phenotypes, including the CVD risk factors.

Next, they applied the bivariate causal mixture model, a statistical tool that estimates the total number of unique and shared genetic variants between pairs of phenotypes and subsequently found a genetic overlap between schizophrenia and some CVD phenotypes, especially smoking and BMI.

Their analysis showed that 8,500 and 8,100 schizophrenia-related genetic variants also influenced smoking initiation and BMI, corresponding to 90 percent and 84 percent overlap, respectively. While the loci shared between schizophrenia and smoking initiation and cigarettes per day had a positive genetic correlation, the overlap with BMI had a negative one, indicating that people with schizophrenia are predisposed to lower BMI and a higher genetic tendency to smoke.

Meanwhile, schizophrenia shared fewer genetic variants with systolic blood pressure, diastolic BP, and type 2 diabetes (T2D), among other CVD-related phenotypes. The shared loci between schizophrenia and these phenotypes had mixed effect directions, which suggested poor genetic correlations.

The authors said these findings indicate that smoking and BMI may be more polygenic than the other CVD phenotypes. While the reasons for differences in polygenicity remain unclear, they believe that brain-regulated behaviors influence smoking and BMI compared to the other CVD phenotypes.

Further, the researchers performed functional analyses of the shared loci, which pointed to genes associated with neurodevelopment and the immune system.

According to Rødevand, the findings about schizophrenia and the increased genetic propensity of smoking are important for patients and clinicians. "It really helps explain why people with schizophrenia struggle to quit smoking. It is not like they are lazy or lack willpower; rather, they have genetic tendencies that make smoking more rewarding," she said.

The authors also said that previous studies have linked nicotine dependence and schizophrenia to variants in the nicotinic acetylcholine receptor (nAChRs), suggesting that smoking nicotine activates nAChRs, which may be an attempt to compensate for the genetically determined dysfunction of nAChRs among patients. However, more work is needed to establish this.

Overall, Rødevand said the findings hold some good news as obesity in schizophrenia patients seems lifestyle-driven, which can be modified through interventions and personalized medical dosage.

Highlighting a significant limitation of the study, Rødevand said that their findings only hold for people of European descent and cannot be generalized to other populations. Moreover, she added that this research didn't address the causes of the shared genetic variants, which could likely be the subject of future studies.