- This cross-disorder genome-wide association study comprised more than 725,000 cases and controls across eight neuropsychiatric disorders
- Genetic correlation analyses revealed that the eight disorders could be divided into three groups that had shared genomics
- 109 single-nucleotide polymorphisms were found to affect two or more disorders, and 23 influenced four or more
- Eleven loci had opposite effects on the risk of two or more disorders
- Loci with pleiotropic effects were distinguished by their involvement in early neurodevelopment and increased expression in the second trimester of fetal development, which persisted throughout adulthood
Genome-wide association studies (GWAS) have revealed a surprising degree of genetic overlap among psychiatric disorders. For example, in 2013 the Cross-Disorder Group of the Psychiatric Genomics Consortium identified genetic loci that have pleiotropic effects (those affecting more than one trait) across five psychiatric disorders in a sample of more than 60,000 people.
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However, the mechanisms of these effects have not been clear. In a new study, Jordan W. Smoller, MD, ScD, director of the Psychiatric and Neuodevelopmental Genetics Unit in the Department of Psychiatry at Massachusetts General Hospital, and colleagues in the Cross-Disorder Group examined a greatly expanded dataset that included three additional psychiatric disorders. In Cell, they report on the shared genetic basis of psychiatric disorders.
In a sample of 232,964 cases and 494,162 controls of European ancestry, the researchers analyzed genome-wide single-nucleotide polymorphism data (SNP) for eight neuropsychiatric disorders:
- Anorexia nervosa (AN)
- Attention-deficit/hyperactivity disorder (ADHD)
- Autism spectrum disorder (ASD)
- Bipolar disorder (BPD)
- Major depressive disorder (MDD)
- Obsessive-compulsive disorder (OCD)
- Schizophrenia (SCZ)
- Tourette syndrome (TS)
Three Groups of Genetically Related Disorders
By modeling genetic correlations among the eight disorders, the researchers identified three groups of disorders that had shared genomics:
- Compulsive behaviors — AN, OCD and TS
- Mood and psychotic disorders — MDD, BPD and SCZ
- Two early-onset neurodevelopmental disorders — ASD and ADHD, plus one disorder from each of the first two groups (TS and MDD)
Variant-level analyses indicated substantial pleiotropy:
- 109 of the 146 genome-wide significant SNPs (75%) were associated with more than one of the eight disorders; of these, 33 had not previously been associated with any of the individual disorders
- 23 genetic risk loci were associated with four or more disorders
- One locus was associated with all eight disorders; it maps within DCC, a gene fundamental to the early development of white matter connections in the brain
Neurodevelopmental Effects Underlie Cross-Disorder Genetics
The researchers found a link between pleiotropy and genetic effects on neurodevelopment for multiple loci besides DCC, including RBFOX1, BRAF and KDM7A, which in prior research have been shown to influence nervous system development. These pleiotropic loci were distinguishable from disorder-specific loci by their involvement in pathways such as neurogenesis, regulation of nervous system development and neuron differentiation.
Risk Loci with Opposite Effects
The research team identified 11 loci that had opposite effects on the risk of two or more psychiatric disorders. For example, three loci had opposite effects on the risk of MDD and SCZ, two had opposite effects on the risk of ASD and SCZ and one had opposite effects on the risk of BPD and MDD.
The research team compared the gene-expression profiles of the 109 pleiotropic risk loci and 37 disorder-specific loci:
- Pleiotropic loci - enriched among genes expressed in neurons, particularly in the frontal or prefrontal regions of the brain
- Single-disorder loci (mainly SCZ) - related to genes preferentially expressed in the first fetal trimester, followed by a decline over the prenatal period and relatively stable levels postnatally. In contrast, average expression of genes related to pleiotropic loci peaked in the second trimester and remained overexpressed throughout the lifespan
It seems that at least two different classes of genetic loci influence psychiatric disorders. First, a set of pleiotropic genes confers generalized liability by acting on early neurodevelopment. Later, this broad genetic risk differentiates into discrete psychiatric syndromes because of the direct and/or interactive effects of additional sets of genes as well as environmental factors.
Still, the genetic influences on psychopathology don't track well with the existing diagnostic categories of mental illnesses. Improved understanding of cross-phenotype genetic effects should lead to better classification, improve risk prediction and aid in the development of drugs and diagnostics.
Learn more about the Psychiatric Neurodevelopmental Genetics Unit