Analysis of shared heritability in common disorders of the brain.
The Brainstorm Consortium. Science. 2018 Jun 22;360(6395). [PMID: 29930110]
Brain disorders can be categorized as neurologic, such as Alzheimer’s disease, or psychiatric, such as attention deficit hyperactivity disorder (ADHD) or schizophrenia. In general, neurological diseases are characterized by unique, observable features of the nervous system, while psychiatric disorders are characterized by behavioral phenomena. In this study, researchers sought to determine the genetic relationships across brain disorders, specifically to determine the genetic similarities and differences between the neurologic and psychiatric categories.
To conduct this study, researchers used genome-wide association data from more than two million participants who either had a psychiatric disorder, a neurological disorder, had no known brain disorder, or had well-defined characteristics of a behavioral or cognitive trait (such as neuroticism, extraversion, or level of cognitive performance). These data were analyzed by The Brainstorm Consortium, a collection of researchers who contributed to a large database on 25 brain disorders.
The researchers found that psychiatric disorders are genetically similar to one another. In particular, schizophrenia shared common risk variants with most other psychiatric disorders, and depression shared genetic similarities with every other psychiatric disease that was tested. Interestingly, they found that ASD was relatively genetically distinct, although it did share some genetic similarities with schizophrenia. In contrast, the researchers found that neurological disorders are more genetically distinct from one another, with the exception of migraine headaches showing significant genetic similarities to ADHD, depression, and Tourette syndrome.
The researchers also sought to determine if brain disorders were related to gene expression patterns corresponding to particular traits. They found that cognitive traits differed across psychiatric disorders with ASD, anorexia, bipolar disorder, and obsessive-compulsive disorder (OCD) showing more positive correlations with cognitive traits. Meanwhile, ADHD, anxiety disorders, depression, and Tourette syndrome showed fewer genetic correlations with cognitive traits. Among personality traits, they found that neuroticism was related to several disorders including anorexia, anxiety disorders, migraine, depression, and OCD. They also found that a low body mass index was associated with anorexia nervosa, while high body mass index was related to ADHD and depression. Lastly, they compared gene expression profiles between neurological disorders and psychiatric disorders and found that neurological disorders are generally genetically different from psychiatric disorders.
The finding that psychiatric disorders are similar to each other is important because it provides evidence that those disorders may share similar symptoms. The researchers note that the relatively small sample sizes for some disorders in this population, including ASD, may account for the lower correlations between these disorders and different traits. The results of this study support a need for careful diagnostic criteria to ensure that diseases are diagnosed properly and provide a potential foundation for more personalized treatments that address overlapping conditions.
Paternally inherited cis-regulatory structural variants are associated with autism.
Brandler WM, Antaki D, Gujral M, Kleiber ML, Whitney J, Maile MS, Hong O, Chapman TR, Tan S, Tandon P, Pang T, Tang SC, Vaux KK, Yang Y, Harrington E, Juul S, Turner DJ, Thiruvahindrapuram B, Kaur G, Wang Z, Kingsmore SF, Gleeson JG, Bisson D, Kakaradov B, Telenti A, Venter JC, Corominas R, Toma C, Cormand B, Rueda I, Guijarro S, Messer KS, Nievergelt CM, Arranz MJ, Courchesne E, Pierce K, Muotri AR, Iakoucheva LM, Hervas A, Scherer SW, Corsello C, Sebat J. Science. 2018 Apr 20;360(6386):327-331. [PMID: 29674594]
The genome is made up of coding regions, which give rise to RNA or protein products, and noncoding regions, which are responsible for regulating gene expression. Genetic variations can occur in either coding or noncoding regions, often leading to diseases and disorders. There are several genetic variations associated with ASD, but only a subset of these occur in protein coding regions. Thus, this study sought to better understand genetic variation in noncoding regions that are associated with ASD.
The researchers compared genetic sequences of 9,274 people, some with and some without ASD, from 2,600 families who had at least one member with ASD. By studying families, the researchers could understand how genetic variations that are associated with the development of ASD are inherited across generations. They focused on genetic variations in noncoding regions of genes (called cis-regulatory elements, or CREs) that structurally disrupt the DNA. The authors sought to identify CRE structural variants, or CRE-SVs, that are associated with ASD.
The researchers found that CRE-SVs accounted for only a small percentage of the total variation in their sample, but associations with ASD were highly significant. This suggests that CRE-SVs may account for a small portion of ASD cases whose genetic origins were previously unidentified. Furthermore, these variants exhibited specific hereditary patterns. In contrast to previous hypotheses that most genetic variations associated with ASD are inherited maternally, CRE-SVs are predominantly inherited from the father. Furthermore, SVs in coding regions were transmitted from mothers and fathers at similar rates; this suggests that mutations in coding regions are inherited differently than those in noncoding regions.
Previously, the role of noncoding genetic variations in ASD were not well-understood. The results of this study suggest that rare, inherited noncoding variants may predispose a child to ASD and that the paternal contributions of genetic variations are more important than previously appreciated. This finding furthers understanding of the underlying genetic causes of ASD and demonstrates the need for further research in genetic variation.
Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap.
Gandal MJ, Haney JR, Parikshak NN, Leppa V, Ramaswami G, Hartl C, Schork AJ, Appadurai V, Buil A, Werge TM, Liu C, White KP; CommonMind Consortium; PsychENCODE Consortium; iPSYCH-BROAD Working Group, Horvath S, Geschwind DH. Science. 2018 Feb 9;359(6376):693-697. [PMID: 29439242]
Brain disorders are complex and are often caused by an accumulation of mutations occurring in multiple genes. Moreover, single or multiple variations in one gene can contribute to many different brain disorders. In this study, researchers wanted to compare gene expression profiles (a comprehensive view of which genes are expressed and at what levels) for individuals with five major psychiatric disorders. They sought to understand both the genes that are expressed normally and the genes that are expressed atypically, for individuals with ASD, schizophrenia, bipolar disorder, depression, or alcoholism. They also wanted to learn more about gene expression profiles in individuals with these conditions relative to individuals without a known psychiatric disorder.
The researchers studied the transcriptome, a profile of an individual’s RNA molecules that reveals details about the expression of genes. By combining several computational techniques, the researchers developed an innovative methodological framework to study shared molecular pathways in brain tissue samples. This framework allowed the researchers to identify patterns of expression across the entire transcriptome.
First, the researchers analyzed published transcriptomes of 700 people with ASD, schizophrenia, bipolar disorder, depression, or alcoholism. To establish a non-neurological comparison group, they also analyzed the gene expression profiles of people with inflammatory bowel disease (IBD). They found overlap in gene expression patterns among people with ASD, schizophrenia, and bipolar disorder, and overlap in gene expression patterns among people with schizophrenia, bipolar disorder, and depression. This finding suggests that some of the same genes are involved in the development of these disorders.
To better understand the significance of commonalities in the gene expression profiles, the researchers aligned the genes with altered expression to gene modules (groups of genes that function in the same biological processes). They found that modules involved in the regulation of neurons and modules involved in some aspects of metabolism were more highly expressed and highly activated in people with ASD, bipolar disorder, and schizophrenia. Subjects with ASD showed differential expression in multiple modules involved in regulation of neurons and in the development of microglia, which are brain cells that stabilize neural connections. They also saw reduction in expression of genes that support the energy demand for neural communication in ASD. Additionally, they identified a neuron-specific module that was enriched in rare gene mutations associated with ASD and was associated with diminished neural connection. These results support previous research that suggests that disruptions in neuronal function and communication are involved in the development of ASD.
This study contributes to knowledge of the genetic associations of different brain disorders. By identifying disorders that share genetic origins, researchers and clinicians can better understand the symptoms and potential treatments for these disorders.
Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder.
Gandal MJ, Zhang P, Hadjimichael E, Walker RL, Chen C, Liu S, Won H, van Bakel H, Varghese M, Wang Y, Shieh AW, Haney J, Parhami S, Belmont J, Kim M, Moran Losada P, Khan Z, Mleczko J, Xia Y, Dai R, Wang D, Yang YT, Xu M, Fish K, Hof PR, Warrell J, Fitzgerald D, White K, Jaffe AE; PsychENCODE Consortium, Peters MA, Gerstein M, Liu C, Iakoucheva LM, Pinto D, Geschwind DH. Science. 2018 De c 14;362(6420). [PMID: 30545856]
Researchers study every element of gene expression — which involves molecules called DNA, RNA, and proteins — to understand how a gene, or a variant of a gene, results in observable traits. One way for scientists to visualize an individual’s gene expression is by looking at the transcriptome, a genetic profile of an individual’s RNA molecules. Transcriptome analyses from the brains of people with psychiatric disorders can supply valuable information about differences in gene expression relative to individuals without a known psychiatric disorder. This type of analysis is important for understanding how brain disorders are related to gene expression and related to each other.
In an earlier study (“Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap,” summarized on page 14), the researchers developed a methodological framework to compare transcriptomes of people with psychiatric diseases to those of neurotypical people. In this study, the researchers expanded upon their previous work to look at differences in expression of the transcriptomes corresponding to individual genes, groups of genes, and isoforms. Isoforms are RNA variants of the same gene that are formed by assembling different coding regions of the gene together. These isoforms thus result in different proteins with different functions.
When the researchers analyzed the expression profiles of people with ASD, schizophrenia, and bipolar disorder, they found that thousands of individual genes were expressed at either higher or lower levels, relative to unaffected controls. Moreover, they found that many differentially expressed genes were common across all three psychiatric disorders, and more than 25% of genes represented in the transcriptome analysis were differentially expressed in at least one disorder. These results suggest that different alterations to shared molecular pathways may contribute to these disorders.
The researchers identified 767, 3,803, and 248 genes with differential transcript expression associated with ASD, schizophrenia, and bipolar disorder, respectively. There was less overlap of isoforms among these three psychiatric disorders, and the researchers speculate that the use of different isoforms may contribute to the differences among these disorders. The researchers also identified non-coding RNA transcripts that were differentially expressed in ASD, schizophrenia, and bipolar disorder. Non-coding RNAs are not translated into proteins, but they often directly bind DNA and modify how genes are expressed. Lastly, the researchers identified several gene modules that are expressed differentially in ASD, schizophrenia, and bipolar disorder, five of which are common among the three disorders.
The novel techniques developed in these two studies provide researchers with a more complete picture of multiple levels of genetic differences in individuals with psychiatric disorders, including ASD. Together, these results reveal additional genetic contributions to the development of these disorders, and explain these disorders share some of the same features. The large number of genes and gene variants involved in these processes may explain how the same disease can manifest very distinctly in different people.
De novo mutations in regulatory elements in neurodevelopmental disorders.
Short PJ, McRae JF, Gallone G, Sifrim A, Won H, Geschwind DH, Wright CF, Firth HV, FitzPatrick DR, Barrett JC, Hurles ME. Nature. 2018 Mar 29;555(7698):611-616. [PMID: 29562236]
Genes are made up of regions that are involved in making proteins (coding regions) and regions that are involved in regulating the gene’s expression (regulatory or noncoding regions). In the past, research on the genetic roots of neurodevelopmental disorders such as ASD has focused on coding regions, but more recent studies have highlighted the importance of variations in the regulatory regions.
The goal of this study was to identify mutations in gene regulatory regions that are related to neurodevelopmental disorders and understand their role in brain development. The researchers focused on de novo mutations, which are “new” gene mutations present in an individual but absent in his/her parents.
The participants of this study were individuals who had a severe, undiagnosed neurodevelopmental disorder and their parents. The researchers analyzed each individual’s genetic profile to identify de novo mutations in regulatory regions, including those associated with genes that are known to be involved in neurodevelopmental disorders.
The researchers identified a large number of mutations that were enriched in genes involved in fetal brain development. The majority of these mutations were found in genes that are evolutionarily conserved and are therefore very likely to be critical for development. However, compared to de novo mutations found in coding regions, the mutations identified in this study are pathogenic (causing or contributing to a disorder) in only a small percentage of cases. The researchers estimated that de novo mutations in noncoding regions may account for only 1 - 3% of undiagnosed individuals for whom a mutation was not found in a coding region.
They also found that the majority of these variants in non-coding regions do not have a dominant pattern of inheritance, meaning that they are not guaranteed to be expressed in offspring even if they are passed down and exist in the child’s genetic code. This is different from pathogenic mutations that are found in coding regions, which typically have a dominant pattern of inheritance.
The results of this study help researchers understand the genetic causes of neurodevelopmental diseases, such as ASD, which can help clinicians with diagnosis. Since the majority of these genetic variants are not dominantly pathogenic, it suggests that the variants identified in this study may account for only a small percentage of developmental disorders.