The genetic links to major depression

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A global research project has mapped out the genetic basis of major depression, identifying 44 genetic variants which are risk factors for depression, 30 of which are newly discovered.

The study, by the Psychiatric Genomics Consortium and co-led in the UK by King’s College London, is the largest study to-date of genetic risk factors for major depression. The research finds that the genetic basis for major depression is shared with other psychiatric disorders such as schizophrenia, and that all humans carry at least some of the 44 genetic risk factors identified in the study.

A significant number of the genetic variants identified in the study are directly linked to the targets of current antidepressant medications. Analysis of the data also suggests that having higher BMI is linked to an increased risk of major depression.

Previous studies have struggled to identify more than a handful of genetic variants associated with depression. By combining seven separate datasets, the research team included data on more than 135,000 people with major depression and more than 344,000 controls.

The study was an unprecedented global effort by over 200 scientists who work with the Psychiatric Genomics Consortium, and was led by the University of North Carolina School of Medicine and the University of Queensland in Australia. Professor Cathryn Lewis and Dr Gerome Breen of King’s College London led the UK contribution, along with scientists and psychiatrists from the Universities of Edinburgh, Cardiff and University College London.

“With this study, depression genetics has advanced to the forefront of genetic discovery,” says Breen from the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) at King’s College London. “The new genetic variants discovered have the potential to revitalise depression treatment by opening up avenues for the discovery of new and improved therapies.”

Major depression affects approximately 14% of the global population and is the biggest contributor to long term disability in the general population worldwide. Yet only about half of patients respond well to existing treatments.
“Depression is an incredibly common disorder that affects millions of people in the UK,’ says Lewis of the IoPPN, who is leading efforts to conduct even larger international studies.

“This study has shed a bright light on the genetic basis of depression, but it is only the first step,” added Lewis. “We need further research to uncover more of the genetic underpinnings, and to understand how genetics and environmental stressors work together to increase risk of depression.”

In the UK, the work was partly-funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London, and the Medical Research Council.

Breen, with other scientists, is currently working on an online tool, for release in the autumn, to allow volunteers with depression to take part in further genetic studies.

Abstract
Major depressive disorder (MDD) is a common illness accompanied by considerable morbidity, mortality, costs, and heightened risk of suicide. We conducted a genome-wide association meta-analysis based in 135,458 cases and 344,901 controls and identified 44 independent and significant loci. The genetic findings were associated with clinical features of major depression and implicated brain regions exhibiting anatomical differences in cases. Targets of antidepressant medications and genes involved in gene splicing were enriched for smaller association signal. We found important relationships of genetic risk for major depression with educational attainment, body mass, and schizophrenia: lower educational attainment and higher body mass were putatively causal, whereas major depression and schizophrenia reflected a partly shared biological etiology. All humans carry lesser or greater numbers of genetic risk factors for major depression. These findings help refine the basis of major depression and imply that a continuous measure of risk underlies the clinical phenotype.

Authors
Naomi R Wray, Stephan Ripke and the Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium

Kings College London material
Nature Genetics abstract


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