The genetics of mental disorders
There are hundreds of different types of mental (or psychiatric) disorders as characterized and defined by the DSM and ICD. Many disorders fall into specific categories, including (but not limited to):
- Anxiety disorders
- Mood disorders
- Psychotic disorders
- Intellectual disabilities
- Developmental disorders
- Personality disorders
- Eating disorders
- Sleep disorders
- Dissociative disorders
- Sexuality-related disorders
- Substance use disorders
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Within these categories, specific disorders include (to name a few examples):
- Major depressive disorder (depression)
- Psychotic disorder
- Primary insomnia
- Autism spectrum disorder (ASD)
- Generalized anxiety disorder (GAD)
- Post-traumatic stress disorder (PTSD)
- Obsessive Compulsive Disorder (OCD)
- Anorexia nervosa
- Body dysmorphic disorder
- Dementia is also included as a mental disorder in DSM / ICD due to the extensive cognitive and personality impairments that occur, besides being primarily a neurological disease.
No psychiatric or mental disorder has a genetic basis or 100% complete heritability, and many environmental factors can strongly influence the likelihood of developing or not developing a particular disorder, despite the presence or absence of genetic elements. Many of these disorders therefore have multifactorial causes – some genetic and others environmental.
In this article, only disorders with a strong genetic basis will be highlighted. Many mental disorders have a high degree of heritability, meaning that the risk of having a disorder if another family member has it increases significantly. Regardless of this, there may be specific genetic mutations or polymorphisms that can predispose individuals to a higher risk of mental disorders without a family history.
Genetic mutations, polymorphisms, or epigenetic changes (which will be discussed below) can alter brain development in ways that alter typical brain wiring. As such, mental disorders can occur at any point in life, such as from birth – like ASD, or later in life in combination with environmental triggers – like bipolar disorder. These predispositions may lower the threshold required for mental disorders to begin in adults compared to “neurotypical” individuals.
One of the most genetically inherited psychiatric disorders is bipolar disorder, which can affect up to 1-4% of the population. Bipolar disorder is characterized by periods of depression followed by periods of abnormally high mood (mania / hypomania). While environmental factors are known to be important causes of bipolar disorder, it is estimated that around 70 to 90% of all cases are attributed to genetic factors.
Specific genetic mutations or polymorphisms (SNPs) within CACNA1C, ODZ4, TRANK1, GNG2, ANK3, TPH2, ITPR2, STEM2, & NCAN have been identified in genetic studies as candidates for increasing the likelihood of developing bipolar disorder. These can be inherited directly from the parents or form de novo during development.
Schizophrenia is believed to have up to 70-80% genetic heritability. Like bipolar disorder, having a first-degree relative with the disorder dramatically increases the risk of developing schizophrenia later in life – although environmental factors are also incredibly important. However, it is difficult to distinguish whether this is due to genetic causes or shared environmental conditions. The cumulative effect of multiple inheritances or de novo mutations / polymorphisms associated with environmental triggers may increase the risk of developing schizophrenia.
For example, copy number variants (CNVs) involved in DiGeorge syndrome (22q11.2) which includes deletions of around 50 genes, including COMT and 17q12 microdeletion syndrome are strongly associated with an increased risk of developing schizophrenia – but are also prevalently co-morbidly associated with ASD and other intellectual disabilities. Other specific genetic mutations involved in schizophrenia include genetic disruptions LAMA2, SETD1A, DPYD, TRRAP, TAF13, ARC & VPS39.
Perhaps the most well-known genetic cause of schizophrenia is DISC1 (disrupted in schizophrenia 1), identified in a Scottish family that suffered from schizophrenia and subsequently in other families, including in America. However, subsequent GWAS studies showed no strong association between DISC1 and schizophrenia, often with mixed results. While DISC1 may not be a gene commonly involved in GWAS studies, it still shows specific mutation level effects in specific families with schizophrenia, for example, the 1q43: 11q14 translocation.
Autism spectrum disorder (ASD)
ASD is a neurodevelopmental disorder usually present from birth. Specific genes have been implicated in ASD, including MECP2, STEM1-3, CACN1E / B2, NRXN, SYNGAP1, UBE3A, KCNQ2 / 3/5, SCNA2 & SYN1 / 3 to name just a few common examples. Many of these genes are linked to specific ion channels and synapses, suggesting abnormal development of synaptic and neural networks. It is therefore not surprising that depending on the genes involved (and the mutations that occur), there is a large degree of clinical and genetic heterogeneity in ASDs due to such a diverse plethora of genetic mutations in them. TSA.
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Many mutations, polymorphisms and epigenetic changes that occur in ASD, also occur in bipolar disorder and schizophrenia as well as other mental disorders (combination of cross disorders). These genes which can have a wide impact and multiple effects from a single gene are called pleiotropic genes. Some of these genes appear to be heavily involved in all of these disorders, including CACNA1C (or related calcium channel genes such as CACNB2), reflecting the common pathogenesis of abnormal synaptic development.
There are many candidates that have been identified in genetic screening studies; however, a notable example includes CDC (SNP rs8084351). The protein product of CDC has a role in axonal growth during neurodevelopment that serves as a key regulator of white matter projections in the developing brain. Loss of function mutations in CDC lead to serious neurodevelopmental complications that involve loss of the mid-commissural pathways and abnormal disorganization of the white matter pathways.
Another key pleiotropic gene is RBFOX1 (SNP rs7193263). RBFOX1 is a regulatory gene involved in the development of neuronal NMDA receptors and voltage-gated calcium channels. RBFOX1 knockout genetic models in mice result in impaired neuronal migration and synapse formation in the developing brain, and this SNP alters these functions as well.
Another highly pleiotropic gene implicated in ASD, schizophrenia and bipolar disorder is NOX4 (SNP rs117956829). NOX4 is a major source of superoxide production in the developing and adult brain as well as promoting the growth of neural stem cells.
In summary, mental (psychiatric) disorders such as bipolar disorder, schizophrenia and ASD have strong genetic bases (mutations, polymorphisms and epigenetic changes) which can be directly inherited from an affected parent, or for de novo during development.
While there are several key genes involved in specific disorders, there are many pleiotropic genes that are involved in all of these disorders rooted in deficits in single genes (eg, CDC) and the calcium channel genes (p. CACNA1C).
Thus, many of these disorders arise due to abnormal neurological development which can either cause disorders from birth (ASD) or strongly predispose individuals to develop psychiatric disorders later in life, particularly in combination with additional environmental factors such as stress.