Weight, Major Psychiatric Disorders Genetically Linked

Michael Vlessides

January 16, 2020

There appears to be a robust genetic link between body weight and major psychiatric disorders, an international research team has concluded.

Using data from more than a 500,000 individuals with major depression, bipolar disorder (BD), and schizophrenia, the investigators showed extensive genetic overlap between body mass index (BMI) and psychiatric disorders.

Interestingly, they found that although the genetic risk variants for major depression and BD were primarily associated with increased weight, the majority of genetic variants for schizophrenia were related to reduced weight.

"This difference in direction was quite interesting to us," principal investigator Ole A. Andreassen, MD, PhD, told Medscape Medical News. "Most of the gene variants overlapping between BMI and depression/bipolar disorder were in the same direction and were associated with higher BMI.

"So if you had a susceptibility for increased BMI, you were also likely to suffer from depression or bipolar disorder," said Andreassen, who is professor of medicine at the University of Oslo, in Norway. "But for schizophrenia, it was the opposite direction: if you were at risk of schizophrenia, you were less likely to be obese."

The study was published online January 8 in JAMA Psychiatry.

Shorter Life Spans

For individuals who suffer major psychiatric disorders, life spans are cut short by 10 to 20 years compared to the general population. This difference, the investigators note, is primarily due to high rates of cardiometabolic risk factors, such as obesity, that are significant contributors to comorbid cardiovascular disease.

Although both behavioral/lifestyle factors and psychopharmacologic medications have significant adverse metabolic effects, the polygenic nature of major psychiatric disorders is becoming increasingly clear. Indeed, the heritability of both obesity and major psychiatric disorders is substantial.

What's more, previous genome-wide association studies (GWAS) have identified common variants involved in BMI and schizophrenia, BD, and major depression. Nevertheless, there are still relatively few data regarding genetic variants that jointly influence both major psychiatric disorders and BMI.

"People with bipolar disorder and major depression seem to have a genetic risk for increased body mass which, together with diet, lifestyle, and medication, can explain the increased weight that many patients experience," the study's first authors, Shahram Bahrami, PhD, and Nils Eiel Steen, MD, PhD, said in a statement.

"There is also this scientific question about how our mental function and physical body interact," said Andreassen.

To help answer these questions, the researchers assessed the extent of overlap between the genetic architectures of major psychiatric disorders and BMI by identifying potential shared genetic loci.

The investigators used a conditional false discovery rate statistical framework to analyze independent GWAS data on 1,380,284 individuals from large study cohorts around the world. These included 82,315 individuals with schizophrenia, 51,710 with bipolar disorder, and 480,359 with major depression.

An additional 795,640 patients with obesity, as determined by BMI, were also included. The data were collected between August 2017 and May 2018, and the analysis began in July 2018.

The study's primary outcome was a list of genetic loci shared with obesity, as determined by BMI, and major psychiatric disorders, as well as their functional pathways.

FUMA, a Web-based platform that facilitates functional annotation of GWAS results, was used to define the independent genomic loci. Advanced statistical methods were used to examine and compare the genetic variants involved in increased body weight and severe mental disorders.

Extensive Genetic Overlap

Perhaps not surprisingly, the study showed that the genetic correlation between BMI obesity and major psychiatric disorders varied significantly (schizophrenia: r for genetic = –0.11; P = 2.1×10-10; bipolar disorder: r for genetic = –0.06; P = .0103; major depression: r for genetic = 0.12; P = 6.7×10-10).

Nevertheless, the investigation also revealed extensive genetic overlap between BMI and psychiatric disorders. There were 63 shared loci for obesity and schizophrenia, 17 for obesity and BD, and 32 for obesity and major depression, at a conjunctional false discovery rate <0.01.

Of the shared loci, 34% (73 of 213) in schizophrenia had risk alleles that were associated with higher BMI (conjunctional false discovery rate, <0.05). In comparison, 52% of shared loci (36 of 69) in BDE had risk alleles associated with higher BMI, as did 57% (56 of 99) in major depression (conjunctional false discovery rate, <0.05). The rest of the shared loci had opposite directions of associations.

Functional analyses of these associations indicated that the overlapping loci are involved in several pathways, including neurodevelopment, neurotransmitter signaling, and intracellular processes. On the other hand, loci with concordant and opposite association directions pointed mostly to different pathways.

Although these findings suggest shared molecular mechanisms between weight regulation and mental illness, there was also a striking difference between disorders.

Although the genetic risk variants for major depression and BD were primarily associated with increased weight, most of the genetic variants in schizophrenia were related to reduced weight.

"So to me, what we can conclude from the study is that increased body weight in schizophrenia seems to be directed mainly by diet, lifestyle, and side effects of medication, but it's a completely different picture with bipolar disorder and depression,” said Andreassen.

Doorway to Personalized Treatment?

Commenting on the findings for Medscape Medical News, Cynthia Bulik, PhD, distinguished professor of psychiatry, University of North Carolina at Chapel Hill, said she was not particularly surprised by the findings.

"One thing genomic research is teaching us is the dividing line of above the neck [for psychiatric traits] and below the neck [for cardiometabolic traits] is indeed arbitrary," said Bulik, who was not involved in the study.

"Aligned with epidemiological findings, these results underscore the importance of considering both metabolic and psychiatric factors when trying to understand and treat mental illness effectively.

"These results also underscore that it is not necessarily a genetic predisposition to obesity that drives the harmful weight gain associated with some antipsychotic medications and underscore the importance of developing medications that have better cardiometabolic profiles that are effective in treating psychosis," Bulik added.

For Andreassen, the results may help to form the basis of future experimental studies in identifying the functional mechanisms involved in obesity among patients with major psychiatric disorders.

"The findings also suggest it is possible to develop prediction tools that can inform treatment choice based on metabolic risk in people with severe mental disorders," he added.

The study was funded by the National Institutes of Health, the Research Council of Norway, the South-Eastern Norway Regional Health Authority, and the Kristian Gerhard Jebsen Foundation. The investigators' relevant financial relationships are listed in the original article. Bulik has disclosed no such relationships.

JAMA Psychiatry. Published online January 8, 2020. Full text

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