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8 Jun 2018

Anttila V et al. Science 2018; 360: eaap8757

Brain disorders often exhibit shared symptoms and considerable epidemiological comorbidity, leading to debate about potential overlaps in their aetiologies. Twin studies have demonstrated that substantial heritability exists among brain disorders, while genome-wide association studies (GWAS) have suggested that individual risk variants can overlap across distinct brain phenotypes, and that these common genetic risk factors contribute to the heritability of brain disorders. Understanding genetic commonalities and distinctions between brain disorders and their related phenotypes may help to further our understanding of their aetiology and pathophysiology. This study by the Brainstorm Consortium used recently developed heritability estimation methods to investigate the degree of overlap of genetic risk factors across 25 brain disorders.

The Brainstorm Consortium was a collaboration of GWAS meta-analysis consortia across 25 psychiatric and neurological brain disorders. The total study sample comprised 265,218 cases of different brain disorders and 784,643 controls, in addition to 1,191,588 cases across 13 brain-related behavioural-cognitive phenotypes* and 4 phenotypes selected to represent known, well-established aetiological processes. GWAS summary statistic data for the 42 disorders and phenotypes were collected and underwent quality control, before linkage disequilibrium score regression, a heritability estimation method developed by the Brainstorm Consortium, was used to estimate common variant heritability and genetic correlations between phenotypes. A weighted least squares regression analysis was then conducted to assess whether differences in study makeup (e.g. sample size) were associated with the magnitude of the correlation estimates.

The results were as follows:

  • Widespread genetic correlations were observed among psychiatric brain disorders, with a particularly high degree of correlation seen between each of ADHD, major depressive disorder (MDD), anxiety disorder, bipolar disorder and schizophrenia (average genetic correlation [rg] = 0.40).
  • In comparison, significant genetic correlations were not observed between neurological disorders, suggesting more distinct aetiologies and potentially greater diagnostic specificity among neurological compared with psychiatric disorders. However, the small sample size for some neurological disorders in this study, and the lack of inclusion of ‘circuit-based disorders’ (e.g. sleep disorders) may limit the generalisability of this finding.
  • Limited genetic correlations were observed between the psychiatric and neurological categories; the only significant cross-category correlations involved migraine, which shared genetic risk variants with ADHD (rg = 0.26, p=8.81×10-8), Tourette’s syndrome (rg =0.19, p=1.80×10-5) and MDD (rg = 0.32, p=1.42×10-22), suggesting that the neurological disorder migraine may share genetic commonalities with some psychiatric disorders.
  • Several significant genetic correlations were observed between the behavioural-cognitive phenotypes and psychiatric disorders, with ADHD, anxiety disorder, MDD and Tourette’s syndrome all showing negative correlations with cognitive measures, whereas anorexia nervosa, autism spectrum disorder, bipolar disorder and obsessive-compulsive disorder showed positive correlations.
  • Among the neurological disorders assessed, Alzheimer’s disease, epilepsy, intracerebral haemorrhage, ischaemic and early-onset stroke, and migraine all showed a significant negative correlation with the cognitive measures.
  • Psychiatric disorders were also significantly correlated with personality and symptom measures. Significant positive correlations were observed between depressive symptoms and ADHD, anxiety disorder, bipolar disorder, MDD and schizophrenia.
  • Among the smoking-related measures, the only significant genetic correlations observed were between never/ever smoked and MDD (rg = 0.33, p=3.10×10-11) and ADHD (rg = 0.37, p=3.15×10-6).
  • Among the additional phenotypes assessed, coronary artery disease showed significant positive correlations to MDD, ischaemic stroke and early-onset stroke, suggesting that these phenotypes share genetic effects. Body mass index was significantly positively correlated with ADHD and MDD, but negatively correlated with anorexia nervosa and schizophrenia. Crohn’s disease showed no correlation with any of the study phenotypes.
  • The only correlation observed between heritability estimates and study makeup-related factors was a modest correlation between age at onset of the disorder and heritability, suggesting a greater degree of heritability in early-onset brain disorders.

The authors concluded that there is a considerable degree of overlap in genetic risk factors for psychiatric disorders, particularly ADHD, MDD, bipolar disorder, anxiety disorder and schizophrenia, indicating possible inter-connected genetic aetiologies among psychiatric disorders, which are not reflected by current clinical diagnostic boundaries. The authors suggested that these findings may provide a basis for restructuring psychiatric nosology and diagnostics. Neurological disorders, however, are more genetically distinct from one another, and additionally share little common variant risk with psychiatric disorders, suggesting that similar phenotypes observed in psychiatric and neurological brain disorders may be the result of independently regulated aetiological pathways. Furthermore, the authors noted that the robust correlations observed between both psychiatric and neurological disorders and cognitive and personality measures could suggest a direct link between the underlying aetiologies governing these phenotypes, and suggested that further research should focus on whether these overlapping genetic contributions could influence treatment choice in patients with brain disorders.

Read more about shared heritability in common brain disorders here

 

*Behavioural-cognitive phenotypes included college attainment, years of education, cognitive performance, intelligence, neuroticism, extraversion, conscientiousness, openness, depressive symptoms, subjective well-being, never/ever smoked and cigarettes per day
Well-delineated aetiological processes represented included immune disorders (Crohn’s disease), vascular disease (coronary artery disease) and anthropomorphic measures (height and BMI)
Common variant heritability was defined as the proportion of phenotypic variance in the sample population that could be explained by an optimal linear predictor, formed using the additive effects of all common autosomal single-nucleotide polymorphisms. Genetic correlation for a pair of phenotypes was defined as the correlation between their optimal genetic predictors. Statistical significance was estimated from block jackknife-based standard errors

Anttila V, Bulik-Sullivan B, Finucane HK, et al [Brainstorm Consortium]. Analysis of shared heritability in common disorders of the brain. Science 2018; 360: eaap8757.

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