Rare Genetic Changes Linked to Depression Risk

In one sentence

A large study of over 320,000 people found that rare genetic changes in certain genes, including one involved in brain energy supply, can increase the risk of depression, and these changes overlap with those seen in autism and schizophrenia.

What the researchers did

Researchers analyzed the exomes (the protein-coding parts of genes) of 320,356 participants from the UK Biobank, a large health database. They looked for rare genetic variants that disrupt protein function and tested whether these variants were more common in people with depression. This is the largest exome study of depression to date.

What they found

• People with a higher burden of rare disruptive variants in genes that normally resist changes (loss-of-function intolerant genes) had a significantly higher risk of depression.
• One gene, SLC2A1, reached exome-wide significance (P=2.96e-7). This gene helps transport glucose across the blood-brain barrier, and its severe mutations cause GLUT1 deficiency syndrome, a rare neurological disorder.
• In total, 30 genes showed suggestive links to depression (false discovery rate <0.1).
• The rare variants associated with depression overlapped with those for developmental disorders, autism, and schizophrenia.
• Common and rare genetic variants contributed additively to depression risk.

What this means for families and therapists

• For families: This study suggests that depression can have a genetic component involving rare variants, which may help explain why some people develop depression despite a lack of obvious environmental triggers. It also highlights a biological link between depression and other neurodevelopmental conditions.
• For therapists: Understanding that depression shares genetic roots with autism and schizophrenia may encourage a more holistic view of mental health, especially when working with autistic clients who may also experience depression.
• For clinicians: If future research confirms these findings, genetic testing might one day help identify individuals at higher risk, but that is not yet ready for routine use.

Limitations and what we don't know yet

• This study is a preprint, meaning it has not yet been peer-reviewed by other scientists.
• The sample is from the UK Biobank, which is not fully representative of the global population (mostly white British, older adults).
• The study identified statistical associations, but does not prove that these rare variants directly cause depression.
• The effects of individual rare variants are small, and many people with depression do not carry these variants.
• The findings need replication in other large, diverse samples.

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This is a plain-language summary of Rare Genetic Changes Linked to Depression Risk by Tian, R., Ge, T. et al., medRxiv (preprint) (2021). Source license: CC_BY_NC_ND. It is not medical advice — talk to a qualified clinician before changing therapy.