A research revealed the genetic origins of schizophrenia

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The first genetic analysis of schizophrenia in an ancestral African population, the South African Xhosa, will be published Jan. 31 in Science. An international group of scientists conducted the research.

The study of schizophrenia was carried out in the Xhosa population because Africa is the birthplace of all humans, yet ancestral African populations have rarely been the focus of genetics research.

The Xhosa do not have an unusually high risk of schizophrenia.

The relative lack of genetics studies in Africa leaves a major gap in understanding human genetics.

Almost 99% of human evolution took place in Africa, after the first modern humans originated and before humans migrated from Africa to Europe and Asia 50,000 to 100,000 years ago.

Because of the lack of studies in Africa, many generations of human genetic history are missing from our understanding of human adaptation and of human disease.

The Xhosa trace their history to the migration of Bantu-speaking people from the Great Lakes region of eastern Africa to southern Africa centuries ago.

The Xhosa now live throughout South Africa and are the largest population group of the Eastern Cape region.

Schizophrenia affects approximately 1% of people in all parts of the world and is one of the leading causes of disability worldwide.

This study revealed that Xhosa individuals with schizophrenia are significantly more likely to carry rare, damaging genetic mutations compared to Xhosa individuals without severe mental illness.

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Synaptic genes collectively carry a significantly greater burden of private damaging mutations in persons with schizophrenia compared to controls. Image is credited to Emily Willoughby/Genetics of Schizophrenia in the South African Xhosa.

Many of the genes disrupted by the rare damaging mutations of these patients are involved in the organization and function of brain synapses.

Synapses coordinate the communication between brain nerve cells called neurons,The organization and firing of neuronal synapses are ultimately responsible for learning, memory and brain function.

The genes and pathways identified by this research inform the understanding of schizophrenia for all human populations, and suggest potential mechanisms for the design of more effective treatments.

The project was led by Jon McClellan, professor of psychiatry, and Mary-Claire King, professor of genome sciences and of medicine, at the University of Washington School of Medicine in Seattle; Dan Stein, professor and head of psychiatry and mental health at the University of Cape Town, South Africa; and Ezra Susser, professor of epidemiology and psychiatry at the Mailman School of Public Health, Columbia University, New York.

The Xhosa community participated in the development and conduct of the research.


Schizophrenia is a severe, highly heritable (h2 = 0.64–0.80) psychiatric disorder that typically emerges in late adolescence or early adulthood (Thaker and Carpenter, 2001Lichtenstein et al., 2009van Os and Kapur, 2009). The peak of illness onset differs by sex regardless of culture, definition of onset, and definition of illness, with onset peaking at 15–25 years of age in men and 20–35 years of age in women (Mendrek and Mancini-Marïe, 2016).

Aligned with these onset peaks, evidence indicates that schizophrenia patients, particularly males, have reduced rate of reproduction (fitness) compared with non-affected populations (Bassett et al., 1996Avila et al., 2001).

Although it has been reported that fertility among relatives of patients with schizophrenia is increased, a large cohort study and meta-analysis identified that this increase was too small to counterbalance the reduced fitness of affected patients (Bundy et al., 2011Power et al., 2013).

In fact, MacCabe et al. (2009) showed that patients with schizophrenia had fewer grandchildren than in the general population, demonstrating that the reduced reproductivity persists into subsequent generations.

This reduction in overall reproduction among those with schizophrenia and their progeny, coupled with high heritability should result in a decrease in schizophrenia according to the evolutionary concept of negative selection.

Negative selection results in the purging of deleterious alleles that contribute to traits that reduce fertility. However, the principle of negative selection seems inconsistent with schizophrenia, which is characterized by both high heritability and reduced fertility (Avila et al., 2001) but relatively stable prevalence in the population, suggesting an evolutionary paradox.

Some have attempted to explain this paradox by proposing that risk alleles for schizophrenia at some time in human history conferred evolutionary advantages (i.e., mating success or reproductivity) (Karksson, 1970Waddell, 1998Turelli and Barton, 2004Nettle and Clegg, 2006), while others have attributed the existence of these risk alleles as a price paid for language and development of the social brain (Crow, 19972000).

The former evolutionary perspective in schizophrenia has been explained by Nettle (2001)Nettle and Clegg (2006), who suggested that schizotypy characteristics could be linked to intelligence, artistic creativity and thus may positively correlate with mating success.

A recent cross-trait analysis of genome-wide association study (GWAS) data supports this notion in that higher polygenic risk scores for schizophrenia predicted creativity (Power et al., 2015).

The latter explanation by Crow proposed schizophrenia as a price the modern human paid for achievement of language (Crow, 1997). This idea was subsequently incorporated in the so-called “by product” hypothesis of schizophrenia by Burns (20042006).

The by product hypothesis relies on the argument that schizophrenia shares a common genetic basis with the evolution of the social brain, representing the abnormal cortical connectivity that occurred approximately 1 to 1.5 million years ago in our ancestors, archaic humans (e.g., Neanderthals, Denisovans).

Other evolutionary theories, such as ancestral neutrality and polygenic mutation-selection balance, have been proposed to explain the evolutionary paradox (Keller and Miller, 2006). However, a consensus has not been reached by evolutionary scientists.

The development of evolutionary genomic tools and the emergence of a critical mass of GWAS data have provided the opportunity to empirically examine the “schizophrenia paradox” and uncover evolutionary mechanisms underpinning the pathogenesis of schizophrenia. Xu et al. (2015) identified the enrichment of schizophrenia SNPs near human accelerated regions (HARs) in the genome that are conserved in primates but have undergone accelerated evolution in humans (pHAR, a type of HARs based on conservation of non-human primates). More recently, Srinivasan et al. (2016) applied a novel evolutionary statistic, the Neanderthal selective sweep (NSS) score, to the largest schizophrenia GWAS dataset (Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2014) and found SNPs associated with schizophrenia were significantly (p = 7.30 × 10−9) enriched in genome regions that were under recent positive selection.

However, recent GWAS findings by Pardiñas et al. (2018) have challenged the notion of selective advantage of schizophrenia risk alleles by demonstrating that these risk alleles have undergone strong background (negative) selection.

To assist in reconciling the current evidence to date, additional evolutionary genomic markers i.e., modern-human-specific (MD) sites and archaic-human-specific (AD) sites have recently become available (Prüfer et al., 2014Figure 1).

These genomic sites provide an opportunity to further interrogate the schizophrenia paradox and examine in more detail the direction of evolutionary mechanisms on SNPs/alleles associated with schizophrenia after modern humans split from archaic humans.

As such, we analyzed the Psychiatric Genomics Consortium (PGC) schizophrenia GWAS data (Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2014) using these new evolutionary markers.

Based on the most recent findings by Pardiñas et al. (2018), we hypothesized that the risk alleles of schizophrenia underwent negative selection after modern humans branched away from Neanderthals and Denisovans.

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FIGURE 1
Schematic illustration of modern-/archaic-human-specific site. In the figure, (A) indicates ancestral allele and (D) indicates non-ancestral (derived) alleles. Modern-human-specific (MD) sites are those sites where Denisovans or Altai Neanderthals have the derived allele and the ancestral allele is fixed or appears at a high frequency (>90%) in modern humans. Archaic-human-specific sites are those sites. For each site, the ancestral/non-ancestral state (allele) was determined via a comparison with the chimpanzee genome.

Discussion

Our findings show that since the modern human lineage split from Neanderthals and Denisovans, risk alleles for schizophrenia but not for other psychiatric disorders, have been progressively eliminated from the modern human genome.

Interestingly, the tendency toward eliminating risk and retaining protective alleles has been identified in not only nominally associated SNPs, but also SNPs that currently have not been associated with schizophrenia (i.e., SNPs with p values > 0.05).

One explanation for this observation is background selection. Background selection is based on the notion that negative selection could decrease the frequency of a deleterious allele, along with the removal of linked variation within the same LD block.

Based on background selection, the elimination of schizophrenia risk alleles may not be the result of their intrinsically deleterious effects, but the negative selection of causal alleles.

The enrichment of schizophrenia SNPs in pHAR regions and NSS regions was identified by Xu et al. (2015) and Srinivasan et al. (2016), respectively.

Srinivasan attributed their observation to the effect of positive selection after the divergence of humans and Neanderthals. However, the most recent study by Pardiñas et al. (2018) has emphasized the role of background selection in the persistence of risk alleles for schizophrenia.

Contrary to the perspective in Srinivasan’s study, Pardiñas et al. (2018) suggested that SNPs under positive selection are less likely to be associated with schizophrenia.

Our findings are consistent with those reported by Pardiñas et al. (2018) in that our results support negative selection and corresponding background selection of schizophrenia risk alleles rather than positive selection.

In Figure 4, we offer a simple preliminary framework that integrates our results within an evolutionary context. Our framework adopts the by-product hypothesis’ notion that the number of schizophrenia risk alleles increased with the development of the social brain, language, and high-order cognitive functions (Crow, 2000Burns, 2004).

Aligned with this notion, we speculate that around 100,000 – 150,000 years ago (Burns, 2004), before the migration of modern humans out-of-Africa (Stringer and Andrews, 1988), there was a “turning point” at which time the number of schizophrenia risk alleles plateaued. Thereafter, risk alleles for schizophrenia have been progressively but slowly eliminated from the modern human genome while undergoing negative selection pressure.

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FIGURE 4
A novel evolutionary framework for the genetic origin of schizophrenia.

Support for our proposed framework would ideally involve evidence suggesting progressive reductions in schizophrenia incidence over the past 100,000 – 150,000 years, along with evidence showing greater schizophrenia polygenic burden among our more distant human ancestors.

However, currently we are limited to DNA obtained from Neanderthals and Denisovans. In addition, the calculation and comparison of schizophrenia polygenic burden in Neanderthals and Denisovans with that observed in modern humans would be an effective approach to validate the proposed framework.

However, the time-frame by which human evolution occurred (e.g., >million years) and the relatively recent operationalization of schizophrenia, pose a significant challenge in evaluating changes in the incidence of schizophrenia from an evolutionary perspective. However, an epidemiological study has suggested the incidence of schizophrenia is declining (McGrath et al., 2008).

Our framework could be strengthened or refined by answers to several outstanding questions. First, when did the “turning point” occur?

We have speculated the occurrence of this event to have taken place 100,000 – 150,000 years ago but more precise estimates would allow for more sophisticated evolutionary models to be created.

Second, how many schizophrenia common risk alleles were present at the turning point?

Our framework assumes the number of schizophrenia risk alleles or polygenic burden was greater among our human ancestors but the extent of this additional burden is unknown.

Third, what is the rate at which common risk alleles have been eliminated and to what extent have other evolutionary mechanisms such as balancing selection or sexual selection counteracted the rate of allele elimination?

Our proposed framework assumes removal of risk alleles has occurred in a static, linear fashion since the turning point. However, to confirm this assumption, DNA from more distant ancestors will be required.

Finally, can a single evolutionary framework explain the genetic origin of schizophrenia?

Our analysis and framework assume that schizophrenia is a unitary disorder. However, it is widely accepted that schizophrenia represents a clustering of various symptoms rather than a unitary disorder and any comprehensive framework is likely to require a combination of models.

As such, our analyses would have ideally been performed on more homogenous populations that shared similar symptoms.

Unfortunately, most public schizophrenia GWAS datasets are limited in the amount of symptom level data available, prohibiting these types of analyses.

Nevertheless, our findings suggest that risk alleles for schizophrenia have been progressively eliminated from the modern human genome, regardless of the presumed symptom heterogeneity within our sample. Future investigations of schizophrenia GWAS data with high quality phenotyping is warranted.

Despite the novelty and strength of our study, we acknowledge several limitations. Due to the limited number of associated SNPs, the study did not examine the enrichment and substitution of schizophrenia susceptibility under strict p-value thresholds.

Novel evolutionary markers encompassing more schizophrenia SNPs are therefore required to further investigate SNPs with genome-wide significance. Second, insertion-deletion (indels) variants were not included in our analysis due to the low number available in our dataset. Indels play regulatory roles in brain functions, thus future studies should explore their contribution to the genetic origins of schizophrenia.

Third, our findings rely on genome information of several archaic humans, but the psychiatric status of the Neanderthal or Denisovan individuals remains unknown. If any of them were affected by psychosis, our findings could be biased.

Finally, other evolutionary models, such as the sexual selection and balancing selection model (Nettle, 2001Del Giudice, 2017), have been proposed to reconcile the evolution paradox in schizophrenia. However, the present study did not empirically evaluate these models because evolutionary markers available are not suitable for testing such evolutionary models.

In sum, we have performed a novel evolutionary analysis using schizophrenia and other psychiatric disorder GWAS data and comparative genome results in modern and archaic humans.

Our study, for the first time, provides experimental evidence supporting the role of negative selection in eliminating risk alleles for schizophrenia but not other psychiatric disorders from the modern human genome.

Based on these theoretical and biological findings, we have proposed a novel evolutionary framework to stimulate further research on the evolutionary paradox and genetic origin of schizophrenia.


Source:
UW Medicine

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