Schizophrenia’s Specificity to Humans

Obsessive dogs, anxious frogs, and depressed hogs – you name it; the list goes on and on. We’ve all heard of animals, particularly some of our closer canine and feline friends, that suffer from psychiatric illnesses. In fact, animals develop the entire gamut of mental disorders, save for one: schizophrenia. According to current literature, psychosis has yet to reported outside of a human substrate. In contrast, obsession, anxiety, and depression have been described in many non-human species.

In the last decade, genome-wide association studies (GWAS) have opened the doors to identifying genetic variations associated with certain diseases and mapping the genetic basis of complex traits. This new investigative approach involves rapidly scanning biological markers across complete sets of DNA to identify risk loci, which are specific locations on genes associated with the disease of interest. Thanks to the Schizophrenia Psychiatric GWAS Consortium, we know that there is a strong genetic risk factor associated with schizophrenia. Tie this in with the fact that psychosis contributes to critically reduced fitness and fecundity, and we’re begging the question: why are genes associated with schizophrenia still out and about, even though they should be heavily selected against? A recent study suggests that perhaps schizophrenia is a cost we face for our complex brains and high-level cognition.

Dr. Joel Dudley of the Icahn School of Medicine at Mount Sinai led the study, which proposed a complex evolutionary mechanism that would explain schizophrenia’s exclusivity, persistence, and prevalence among the human population. In particular, the study looked at segments of DNA dubbed human accelerated regions (HARs). The HARs comprise 49 segments of the human genome that, though present in all vertebrates, are drastically different in humans. It is thought that some of these regions may contribute to human-specific traits. Unlike the prototypical gene, a HAR’s role is not only to produce proteins, but also to help regulate neighboring genes.  

Dr. Dudley and company suspected a link between HARs and schizophrenia. They set out to determine whether any schizophrenia-associated genes were close to HARs on the human genome. Lo and behold, they found evidence in support of their hypothesis, suggesting that HARs help to regulate genes associated with schizophrenia. Furthermore, they found that HARs-associated schizophrenia genes were subject to increased selective pressure compared to other schizophrenia genes. The implication is that perhaps the human HARs genotype is beneficial to us in some way despite their encapsulated risk of schizophrenia.

A final piece of information linking much of the study together was an association found between the HARs of interest and neurotransmission of GABA, the brain’s chief inhibitory neurotransmitter. This connection contributes to a growing body of evidence implicating GABA as a key component in the pathophysiology of schizophrenia. The idea behind this theory is simple: a lack of inhibition by GABA renders the brain rampant with activity and contributes to common psychotic symptoms such as hallucinations, disorganized speech, and delusions. Without GABA, the schizophrenic brain is without control.

Psychosis is not nearly as cut and dry as researchers and clinicians would prefer. Symptoms of schizophrenia vary from individual to individual, and this devastating illness spans a wide gamut. In fact, many affected individuals from non-western cultures report a positive relationship with auditory hallucinations – the voices in their heads. Though decades of research have shown a definite genetic component to schizophrenia, environmental context can play into how this illness manifests. 

The take-home point is that humans are complex beings with exceptionally high-level thinking and advanced problem solving abilities, due in part to underlying genetic mechanisms including human accelerated regions. Our potential for complex function allows for complex malfunction.

 

More than 100 issues of JYI have been published since the journal was founded in 1997.
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