Although mental disorders have multifactorial causes, genetics can explain some of them, yet this field remains largely unexplored in terms of guiding diagnoses and treatments. In the largest study of its kind ever conducted and published in the journal Nature, an international consortium of researchers compared common genetic variants in 14 psychiatric conditions and classified them into five major groups. These groups, referred to in the study as factors, share genetic variants with each other.
"Psychiatric disorders have symptoms in common, which makes diagnosis difficult, as it's still based solely on clinical evaluation. This work shows, from a genetic point of view, what clinicians have already observed in relation to schizophrenia and bipolar disorder, for example, which co-occur and which, biologically, may represent a continuum, with 80% of the genetic variants shared between the two conditions," explains Diego Luiz Rovaris , a professor at the University of São Paulo's Biomedical Sciences Institute (ICB-USP) in Brazil. Rovaris is supported by FAPESP and is participating in the study.
Factor 1 includes compulsive disorders such as anorexia nervosa and obsessive-compulsive disorder (OCD), as well as Tourette syndrome and anxiety disorders, which are related but to a lesser extent. Factor 2 is defined by schizophrenia and bipolar disorder, which share, among other characteristics, gene expression in excitatory neurons and in regions of the brain involved in processing reality.
Factor 3, which is linked to neurodevelopment, includes autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), and Tourette syndrome to a moderate extent. This factor is largely explained by genes that express themselves very early in brain development. In 2023, Rovaris was part of the group that published the discovery of 76 ADHD-related genes in Nature Genetics .
Factor 4 includes internalizing conditions such as depression, anxiety disorders, and post-traumatic stress disorder (PTSD). The most highly expressed genes in this group are linked not to neurons but to glia, which are support cells. This suggests that depression and anxiety are more closely linked to brain infrastructure maintenance than to neurons that transmit signals.
Finally, factor 5 is related to substance abuse, including alcohol use disorder, nicotine dependence, cannabis use disorder, and opioid use disorder. In this factor, variants were found in genes encoding the enzyme that breaks down alcohol and the receptors that respond to nicotine.
This factor was most closely associated with socioeconomic indicators, such as income and cognitive ability. This suggests that it may be more closely linked to environmental factors than the other factors analyzed.
"Our genome has rare and common genetic variants. This study looked only at the common ones, more specifically single nucleotide polymorphisms [SNPs]. This is a category of variants with a major impact on multifactorial diseases, such as psychiatric conditions," explains Sintia Belangero , a professor at the São Paulo School of Medicine at the Federal University of São Paulo (EPM-UNIFESP), who also participated in the study and is supported by FAPESP .
In 2022, Belangero was part of the group that published the discovery of more than 100 genes related to schizophrenia in Nature (read more at agencia.fapesp.br/38467 ).
Of all the analyzed conditions, Tourette syndrome shares the fewest genetic characteristics with other disorders. Eighty-seven percent of these characteristics are unique to the condition. Researchers also found the so-called P factor, a set of genetic variants related to all 14 conditions analyzed. The study compared more than one million diagnosed cases with each other and with people without psychiatric conditions.
The results may help in the search for new treatments, including through drug repurposing. In this approach, a drug approved for one condition is applied to another, which already occurs for some psychiatric diseases.
Data cross-referencing
Belangero and Rovaris point out that the analyses were restricted to populations of European origin due to the disproportionate amount of data from these populations in this type of study. However, they say this is changing as groups in Brazil work to provide data on the Brazilian population through the Latin American Genomics Consortium ( LAGC ) and increase Latin America's representation in such studies.
This initiative is affiliated with the Psychiatric Genomics Consortium ( PGC ), which collects genomic data related to psychiatric conditions in populations around the world.
The method used, known as a genome-wide association study (GWAS), robustly reinforced what other genetic evidence and clinical data had already suggested, allowing for further studies on psychiatric conditions.
In a previous study , Rovaris, Belangero, and other authors concluded that 85% of participants in psychiatric genetics research have European ancestry.
Neurodiversity
According to an estimate published in 2005, half of the world's population will meet the criteria for at least one mental disorder during their lifetime.
In a commentary in the same issue of Nature that published the study, Abdel Abdellaoui, a professor at the University of Amsterdam in the Netherlands, notes that much of the genetic variation associated with clinical disorders overlaps with normal traits such as cognition, sleep, personality, and social behavior. He also notes that not all associations are negative.
"Psychiatric disorders seem to arise more frequently at the extremes of this genetic variation continuum, when certain gene and life experience combinations overlap unfavorably. This should reposition mental illness not as part of defective biology but as the intersection of natural variation and environmental stress," he writes.
Among the study's authors is Euripedes Constantino Miguel , a professor at the USP Medical School and coordinator of the Center for Research and Innovation in Mental Health ( CISM ), an Applied Research Center ( ARC ) of FAPESP.
Also participating from EPM-UNIFESP were Vanessa Ota , Ary Gadelha , Rodrigo Bressan , Marcos Santoro , Cristiano Noto, Carolina Carvalho , and Pedro Mario Pan . The other Brazilian authors involved are from the Hospital de Clínicas in Porto Alegre and the Federal University of Rio Grande do Sul (UFRGS).
About São Paulo Research Foundation (FAPESP)
The São Paulo Research Foundation (FAPESP) is a public institution with the mission of supporting scientific research in all fields of knowledge by awarding scholarships, fellowships and grants to investigators linked with higher education and research institutions in the State of São Paulo, Brazil. FAPESP is aware that the very best research can only be done by working with the best researchers internationally. Therefore, it has established partnerships with funding agencies, higher education, private companies, and research organizations in other countries known for the quality of their research and has been encouraging scientists funded by its grants to further develop their international collaboration. You can learn more about FAPESP at www.fapesp.br/en and visit FAPESP news agency at www.agencia.fapesp.br/en to keep updated with the latest scientific breakthroughs FAPESP helps achieve through its many programs, awards and research centers. You may also subscribe to FAPESP news agency at http://agencia.fapesp.br/subscribe .
