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Psychiatric Disorders, Body Mass Index Share Genetic Loci, Study Finds

NEW YORK – A number of genetic loci associated with body mass index are also linked to psychiatric disorders like schizophrenia, major depression, and bipolar disorder, a new analysis has found.

People with psychiatric conditions often have lifespans that are 10 to 20 years shorter than unaffected individuals, a difference that is thought to be in part due to cardiometabolic comorbidities but also due to side effects of antipsychotics and other drugs. Still, as both body mass index and major psychiatric conditions are influenced by numerous genetic loci, a team led by University of Oslo researchers sought to examine any overlap between those loci. 

As they reported today in JAMA Psychiatry, the researchers used summary statistics from genome-wide association studies to explore the genetic overlap between BMI and the psychiatric disorders schizophrenia, major depression, and bipolar disorder. This analysis of more than 1 million individuals found more than 110 shared genetic loci between the disorders and BMI. Some risk alleles were linked to higher BMI, while others were linked to lower BMI.

"Here, we demonstrate extensive genetic overlap between BMI and psychotic and affective disorders with a striking pattern of bidirectional associations, suggesting a complex interplay of metabolism-related gene pathways in the pathophysiology of [schizophrenia, bipolar disorder, and major depression]," Oslo's Shahram Bahrami and his colleagues wrote in their paper

The researchers analyzed GWAS summary statistics from GIANT consortium, UK Biobank, Psychiatric Genomics Consortium GWAS, and 23andMe GWAS projects. In all — after trying to avoid sample overlaps — they analyzed data from 1.3 million individuals, including people with schizophrenia, bipolar disorder, and major depression, as well as controls. 

Through a series of statistical analyses, they uncovered polygenic overlap between these conditions and BMI. In particular, BMI and schizophrenia shared 63 genetic loci, while BMI and bipolar disorder shared 17 genetic loci and BMI and major depression shared 32 loci. 

The shared alleles did not always work in the same direction, the researchers noted. About a third of the shared loci in schizophrenia were associated with higher BMI, while just more than half and nearly 60 percent of shared alleles in bipolar disorder and major depression were associated, respectively, with higher BMI. This indicates there is a differing genetic liability to weight gain in each of these conditions, and that other factors than disease-specific genetics — such as treatment approach, diet, and lifestyle — may contribute to weight gain among individuals with psychiatric conditions, especially schizophrenia. 

Still, the researchers' findings indicated there is overlapping genetic architecture between psychiatric conditions and BMI, which they said was supported by previous clinical and epidemiological findings.

By annotating the shared loci, they found that these loci were enriched in pathways involved in central nervous system development but also hormone, GABAergic, and glutamatergic signaling. This, they noted, indicates that there are complex interactions between these pathways that influence psychiatric conditions and BMI. 

It additionally suggests that BMI regulation is in part controlled through brain-regulated mechanisms and that similar mechanisms could be at play in behavior associated with both BMI regulation and psychiatric conditions.

"The findings have implications for the discovery of drugs with fewer adverse events and potential future individualized treatment to reduce weight gain," the researchers added.

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