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THE BRAINSTORM CONSORTIUM
(Anttila, V. et al.- 649 co-authors: Oades (RDO)
360th),
Analysis of shared heritability in common disorders
of the brain Science,
360, eaap8757. http://dx.doi.org/10.1126/science.aap8757
Abstract
INTRODUCTION:
Brain disorders may exhibit shared symptoms and substantial epidemiological
comorbidity, inciting debate about their etiologic overlap. However,
detailed study of phenotypes with different ages of onset, severity,
and presentation poses a considerable challenge.
Recently developed heritability methods allow us to accurately
measure correlation of genome-wide common variant risk between 2 phenotypes
from pools of different individuals and assess how connected they, or
at least their genetic risks, are on the genomic level.
We used genome-wide association data for 265,218 patients and
784,643 control participants, as well as 17 phenotypes from a total
of 1,191,588 individuals, to quantify the degree of overlap for genetic
risk factors of 25 common brain disorders.
RATIONALE:
Over the past century, the classification of brain disorders has evolved
to reflect the medical and scientific communities’ assessments
of the presumed root causes of clinical phenomena such as behavioural
change, loss of motor function, or alterations of consciousness. Directly
observable phenomena (such as the presence of emboli, protein tangles,
or unusual electrical activity patterns) generally define and separate
neurological disorders from psychiatric disorders. Understanding the
genetic underpinnings and categorical distinctions for brain disorders
and related phenotypes may inform the search for their biological mechanisms.
RESULTS:
1/ Common variant risk for psychiatric
disorders was shown to correlate significantly, especially among attention
deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive
disorder (MDD), and schizophrenia.
2/ By contrast, neurological disorders
appear more distinct from one another and from the psychiatric disorders,
except for migraine, which was significantly correlated to ADHD, MDD,
and Tourette syndrome.
3/We demonstrate that, in the general population,
the personality trait neuroticism is significantly correlated with almost
every psychiatric disorder and migraine.
4/ We also identify significant genetic
sharing between disorders and early life cognitive measures (e.g., years
of education and college attainment) in the general population, demonstrating
positive correlation with several psychiatric disorders (e.g., anorexia
nervosa and bipolar disorder) and negative correlation with several
neurological phenotypes (e.g., Alzheimer’s disease and ischemic
stroke), even though the latter are considered to result from specific
processes that occur later in life.
5/ Extensive simulations were also performed
to inform how statistical power, diagnostic misclassification, and phenotypic
heterogeneity influence genetic correlations.
CONCLUSION:
a) The high degree of genetic correlation
among many of the psychiatric disorders adds further evidence that their
current clinical boundaries do not reflect distinct underlying pathogenic
processes, at least on the genetic level.
b) This suggests a deeply interconnected
nature for psychiatric disorders, in contrast to neurological disorders,
and underscores the need to refine psychiatric diagnostics. Genetically
informed analyses may provide important “scaffolding” to
support such restructuring of psychiatric nosology, which likely requires
incorporating many levels of information.
c) By contrast, we find limited evidence
for widespread common genetic risk sharing among neurological disorders
or across neurological and psychiatric disorders.
d) We show that both psychiatric and neurological
disorders have robust correlations with cognitive and personality measures.
Further study is needed to evaluate whether overlapping genetic contributions
to psychiatric pathology may influence treatment choices. Ultimately,
such developments may pave the way toward reduced heterogeneity and
improved diagnosis and treatment of psychiatric disorders
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