How might the genetic identification of mental disorders vary across geographical spaces, cross culturally and through time?

Sedera Moore, Department Of Biology, Howard University '16


Introduction

Genetics are used to link and identify a variety of functions that occur in the body. Moreover, genetics can be utilized to analyze ailments, such as the various mental disorders that people suffer from daily. While the diagnosis of mental disorders is not a rare concept, there are dissimilarities in the causes of people being diagnosed. However, before discussing variations in the genetic identification of mental disorders, it is important to have an understanding of what mental disorders are. This paper will introduce the concept of mental disorders and provide several examples in regards to the variation of mental disorders across geographical spaces, cross culturally, and through time relating to genetic identification, exposed environment, and specific ethnic groups.

Mental disorders are illnesses that stem from a malfunction in the brain. For the purpose of simplification, we will first view the term mental disorder as two separate entities. The word “mental” relates to the mind and one’s intellectual activity. The term “disorder” conveys the presence of an irregularity or disturbance. Combining these separate definitions, a mental disorder is an irregularity or disHow might the genetic identification of mental disorders vary across geographical spaces, cross culturally and through time?

 Mental disorders are not uniformly dispersed across the globe. The magnitude of people diagnosed with mental disorders varies across geographical spaces, cross culturally, and throughout generations. A prime example of this variation in the genetic identification of mental disorders can be seen in in an article titled, “The role of the genetic variation in the causation of mental illness: an evolution-informed framework.

Genetic variation an evolution-informed framework

    According to this article, mental illness usually begins to emerge early in the reproductive age and is linked to a considerable amount of procreative disadvantages. In theory, these procreative disadvantages observed by mental illnesses should lead to these disorders having strong negative selection pressures. On the contrary, mental disorders appear to be a common diagnosis; specifically in twin studies which show a strong correlation between the disease’s etiology and its genetic contribution. This article discussed a proposed hypothesis for identifying mental illness, suggesting that the genetic contribution to mental illness results from gene-environment interactions and rare genetic variants.  

Depression and Gene-Environment Interactions

An example where mental disorders may be contributed with certain environmental influences can be seen with depression. Depression is a mental health condition that underlies a mood disorder causing severe sadness and affecting a person’s normal daily functionings.  Recent discoveries (from Caspi et al., 2003) show that individuals with one or two short alleles of the serotonin transporter gene promoter polymorphism (5-HTTLPR) have an increased susceptibility to depression when encountering stressful life events. These results appeared when the 5-HTTLPR gene, stress, and depression were observed simultaneously over a course of 5 years prior to the onset of the depression. Depression severity displayed episodes at an average duration of 24 months and were associated with loss, threat, and humiliation. Overall, the outcome of this study revealed that the depression most likely stems from life events that occurred after the onset of the disorder.  

Increased life expectancy and Alzheimer’s disease

    Throughout time, life expectancy has increased globally. According to the National Institute on Aging, “The dramatic increase in average life expectancy during the 20th century ranks as one of society’s greatest achievements. Although most babies born in 1900 did not live past age 50, life expectancy at birth now exceeds 83 years in Japan—the current leader—and is at least 81 years in several other countries. Less developed regions of the world have experienced a steady increase in life expectancy since World War II, although not all regions have shared in these improvements. One notable exception is the fall in life expectancy in many parts of Africa because of deaths caused by the HIV/AIDS epidemic. The most dramatic and rapid gains have occurred in East Asia, where life expectancy at birth increased from less than 45 years in 1950 to more than 74 years today.” There is possibly a positive correlation between an increase in some mental disorders and higher life expectancies. 

As humans continue to live longer, they can be affected by different mental disorders later on in life. This is seen in people with Alzheimer’s disease. Alzheimer’s disease is a degenerative mental disorder that progressively attacks the brain’s neurons.  The targeted age group for Alzheimer’s disease begins around age 65. A study done at Duke University determined that there has been approximately a fourfold increase in the rate of people being diagnosed with Alzheimer’s: escalating from 35/1000 in 1991 to a striking 135/1000 in 1999. When isolating this data by racial group and gender, the Alzheimer’s disease rate increased by a factor of 4.7 in African American women in comparison to a factor of 2.3 for White women. There is currently an estimated 5.1 million people living with Alzheimer’s disease in the United States for 2015. Due to an increase in life expectancy through time, this disease is expected to triple in its effect rising from 5.1 million to an anticipated 13.8 million by 2025. 

Racial Health Disparities and Schizophrenia

Similar to Alzheimer’s disease, variations are seen in the diagnosis of mental illness when looking at a correlation between race and the mental disorder schizophrenia. Specifically, certain health disparities are observed between blacks and whites, in terms of schizophrenia, and studies show that blacks are more likely to be diagnosed than their white counterparts. Schizophrenia is a severe brain disorder in which people interpret reality abnormally. Moreover, schizophrenia may result in some combination of hallucinations, delusions, and extremely disordered thinking and behavior. A Child Health and Development Study examined the schizophrenia health disparity through study subjects conceived from black and white women from a common area. 

These women were enrolled during pregnancy at the Alameda County Kaiser Permanente Medical Care Plan clinics over the course of 6 years (1959-1966). During this time frame, there were 19,044 live births and of these live births 12,094 progeny were selected to be observed in the study. These offspring were charted for 16 years (1981-1997) with the purpose of addressing if African Americans have higher rates of schizophrenia than whites. In addition, the study looked into whether this expected risk increase is arbitrated by the socioeconomic status (SES) background of the offspring. The title of this study was “Race and risk of schizophrenia in a US birth cohort: another example of health disparity?”

An analytic sample of 2,128 African American women and 4,508 White women were used for the data comparison. The fathers of these children were mainly the same race as the mothers (98% for African Americans and 92% for Whites). The remaining offspring were excluded from data analysis for reasons including; death, adoption, loss to follow up, and exclusion of sibling information. Thus, the resultant sample consisted of 6,636 women; approximately 68% White and 32% African American. From this sample 62 cases of schizophrenia spectrum disorder (SSD) were diagnosed; 32 African Americans (22 men and 10 women) and 30 Whites (20 men and 10 women). Moreover, the study states that “The proportion of SSD cases diagnosed with schizophrenia was higher among African Americans (23/32) than among whites (15/30). Within diagnostic categories, the mean age at index treatment was similar for African American and white cases (22.5 and 23.9 years for schizophrenia, 26.3 and 26.8 years for other SSDs, respectively).” 

When comparing these two groups, variation is present in the magnitude of people affected by this mental disorder by race. Additionally, the socioeconomic status background of these diagnosed groups were observed. There was minimal correlation seen between in the higher percentage of African American’s diagnosed with schizophrenia in comparison to whites and socioeconomic status. Prior to factoring in socioeconomic status (SES) African Americans were 3-fold more likely to get schizophrenia than whites; however, succeeding the SES factorization, African Americans were 2-fold more times as likely. Based on this information, socioeconomic status may partially coincide with race when observing increased risks of schizophrenia. 

Genetic Identification of the Five Spectrum Disorders

Furthermore, another study that looked into the genetic identification of mental disorders focused on five specific mental disorders; autism spectrum disorder, attention deficit-hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia. This study analyzed single-nucleotide polymorphism (SNP) data for 61,220 people of European ancestry; 33,332 cases and 27,888 controls, for the purpose of characterizing the allelic contribution of each disorder. Significant data was observed on a number of loci theoretically linked to schizophrenia and bipolar disorder in previous studies. The loci were located near MIR137 (microRNA 137), TCF4 (transcription factor 4), the MHC region on chromosome 6, and SYNE1 (spectrin repeat containing, nuclear envelope 1). Based on results from polygenic risk scores the loci showed cross disorder associations; particularly between adult-onset disorders. 

Moreover, Genome Wide Association Studies (GWAS) produced data that linked 4 SNPs to bipolar disorder (rs937l601, rs10994397, rs4765914, and rs12576775) and 10 SNPs to schizophrenia (rs2021722, rs1625579, rs12966547, rs7914558, rs11191580, rs7004633, rs10503253, rs17662626, and rs17512836). Additionally, a meta-analysis done for the five disorders revealed results for regions at a genome-wide significance threshold (p<5×10−8). The SNPs on chromosome 3 (rs2535629) and chromosome 10 (rs11191454 and rs2799573) showed that these SNPs had a supported effect for all five of the disorders (autism spectrum disorder, attention deficit-hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia). The meta-analysis for chromosome 12 revealed the rs1024582 SNP specific to bipolar disorder and schizophrenia. 

Bipolar and Schizophrenia disorder CACNA1C gene

Lkewise, a different study looked into a bipolar and schizophrenia disorder risk gene CACNA1C: where the CACNA1C gene is highly expressed in the brain. When tested for genetic variation, it was proposed that the representative SNP (the rs2159100 for rs1006737) plays a role in the magnitude at which the CACNA1C gene is expressed. According to the results, “carriers of the risk-associated genotype (AA) had highest expression, with heterozygotes (GA) having intermediate expression and the common allele carriers (GG) having the lowest expression (P = .002 for linear regression analysis).” Additionally, there was dissimilarity in the CACNA1C gene expression in terms of race/ethnicity. This was the case for whites and African Americans. The study concluded that this variation is possibly a result of a difference in minor allele frequency (26% for whites and 45%, for African Americans). The risk associated alleles are associate with increased levels of CACNA1C mRNA. 

Furthermore, the study shows that calcium channel defects may add to the genetic cause of bipolar disorder and schizophrenia by changing the functional activity of the brain’s electrical systems. This data corresponds to the COMT, GRM3, BDNF, and DISC1 genes that have been associated with neural circuitry diagnosis and pattern effects. The article states that, “Investigations of the N-back working memory task have shown that patients with schizophrenia and their healthy siblings have increased prefrontal cortical activity for a given level of performance, suggesting that inefficiency in this circuitry is heritable and a good intermediate phenotype related to genetic risk for schizophrenia. Analogous studies have been performed among patients with bipolar disorder using neuroimaging tasks that target mood circuitry in the temporal lobe. Other studies have targeted serotonin signaling genes and have found that healthy subjects who are carriers of the short allele of the serotonin transporter, the target of drugs that treat the mood symptoms of bipolar disorder, have higher ratings of anxiety and depression, and have greater activation of the limbic circuitry, similar to this data.” 

These results indicate that there is a genetic factor in the diagnosis of schizophrenia and bipolar disorder. Not only did the patients already diagnosed with schizophrenia have increased prefrontal cortical activity, so did their undiagnosed healthy siblings. The association of this increased prefrontal cortical activity between the patients and their siblings shows that schizophrenia may be linked to a hereditary source. Moreover, healthy people that carried the short allele of the serotonin transporter (target of drugs that treat bipolar disorder) showed increased levels of anxiety and depression. This is indicative of the short serotonin transporter allele playing a role in bipolar disorder. Bipolar disorder displays symptoms of high anxiety and depression levels. Linking this to short allele builds a connection to the genetic identification of the bipolar disorder.    

Bipolar and Schizophrenia disorder at several genes

Another study looked into the genes responsible for schizophrenia and bipolar to attribute them as implications of psychiatric disease studies. The NRG1 gene has been linked to schizophrenia following multiple studies that provided evidence supporting this association. These studies include; a systematic study of 8p21-22 and a multi-marker haplotype at the 5’ end of the NRG1 gene. The binding protein dysbindin (DTNBP1) has also been implicated as being associated with schizophrenia, however, studies of dysbindin in association with bipolar disorder have not displayed significant results. According to the article researchers, “found no significant associations in bi-polar disorder as a whole but found modestly significant evidence for association in the subset of bipolar cases with predominantly psychotic episodes of mood disturbance with a similar pattern of findings to that seen by this group in schizophrenia. His finding suggests that variation in dysbindin confers risk to psychosis rather than to mood disorders per se, although replication is required.” The results from the binding protein dysbindin shows the variation in the genetic identification of mental disorders. Dysbindin marks significant outcomes in terms of the mental disorder schizophrenia however, it this is not the case for bipolar disorder.  This may be a consequence of different mechanisms attributing to the mental disorders. 

Similarly, the G72(DAOA)/G30 locus, which is best associated with bipolar disorder, shows specific variants connected to the disorder. Previous studies of the G72(DAOA)/G30 locus were performed by association mapping in the linkage region on chromosome 13q22-34. Similar results were observed between French Canadian and Russian populations at two genes; the G72 (D-amino acid oxidase activator) and the G30 gene (DAOA antisense RNA 1).  According to the study, “They found associations in French Canadian and Russian populations in markers around two novel genes, G72 and G30, which are overlapping but transcribed in opposite directions. G72 is a primate-specific gene expressed in the caudate and amygdala. Using yeast two-hybrid analysis, evidence for physical interaction was found between G72 and D-amino-acid oxidase (DAO). DAO is expressed in the human brain, where it oxidizes D-serine, a potent activator of NMDA glutamate receptor. Co-incubation of G72 and DAO in vitro revealed a functional interaction with G72 enhancing the activity of DAO. Consequently,G72 has now been named D-amino-acid oxidase activator (DAOA) Associations between DAOA and schizophrenia have subsequently been reported in samples from Germany, China, Ashkenazi Jews, and both the United States and South Africa, as well as a small sample of very early onset psychosis subjects from the United States. There is no consensus concerning the specific risk alleles or haplotypes across studies.”

Likewise, this study also looked at the effects of the DISC1 gene in schizophrenia. This gene was associated with broad phenotypic results in connection to bipolar disorder, schizophrenia, and recurrent depression. In a balanced chromosomal translocation (1;11)(q42;q14.3), two DISC1 genes were disturbed (the DISC1 and the DISC2 gene) at chromosome 1.  The article states that, “A small pedigree has recently been reported in which a 4bp deletion in exon 12 of DISC1 cosegregates with schizophrenia and schizoaffective disorder.” The final gene discussed in this article was the brain derived neurotrophic factor gene (BDNF) in association with mood disorders; specifically bipolar disorder. It states in the text, “Only one frequent, non-conservative polymorphism in the human BDNF gene has been identified, a single nucleotide polymorphism (SNP) at nucleotide 196 within the 5’ pro-BDNF sequence that causes an amino acid substitution of valine to methionine at codon 66 (Val66Met) and may have a functionally relevant effect by modifying the processing and trafficking of BDNF.” Three positive results were recorded in a family based association study in conjunction with the BDNF gene. The family was Caucasian of European-American origin and consisted of two bipolar adults and one small onset child. Each family member displayed an over-transmission of the Val66Met allele. According to these results, this variant may attribute to the susceptibility of bipolar disorder in certain individuals. 

Variant Genetic Identification of OCD

Correspondingly, another study looked into the genetic identification of obsessive compulsive disorder (OCD). OCD is a mental health disorder categorized by unreasonable thoughts and fears (obsessions) that lead to repetitive behaviors (compulsions) sufficient enough to affect a person’s normal daily functioning. The goal of this study was to “determine the role of genetic variation of SLC1A1 in OCD in a large case-control study and to better understand how SLC1A1 variation affects functionality.” This experiment consisted of 987 people; 325 obsessive compulsive disorder subjects and 662 ethnically and sex-matched controls. Significant results were observed in association of 3 genetic markers (rs3087879, rs301430, and rs7858819) in obsessive compulsive disorder using haplotype analysis. A haplotype labeled “H4” was nearly twice more common in OCD cases than in the control cases; the H4 OCD cases had a haplotype frequency of 9.4% compared to the controls haplotype frequency of 5.1%. Also, the rs393331 SNP was associated with an OCD-hoarding sub-phenotype as assessed by 2 independent, validated scales. This correlates with SLC1A1 gene expression and shows the association of the quantative trait loci with obsessive-compulsive disorder.

Conclusion

    There is evident variation in the genetic identification of mental disorders across geographical spaces, cross culturally, and through time. Studies have shown that an abnormal production of certain genes are recognized as a possibly cause of increasing a person’s susceptibility to some mental disorders. Additionally, studies have presented variation in the racial/ethnic groups affected by a mental illness. Specifically, multiple studies have recognized African Americans as a primary victims of schizophrenia. Moreover, the exposed environment of individuals have been linked to their predisposition to mental illness. Hopefully, future studies can further target the mechanisms causing mental disorders and acquire prevention techniques.***


References

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Sedera Moore is from Philadelphia, Pennsylvania and will be graduating from the Department of Biology at Howard University in May 2016. In the summer of 2014, Sedera interned with DuPont Experimental Station in Wilmington Delaware where she served as an Associate Investigator conducting bioassays collaboratively as well as independently for DuPont Seed Coatings. This summer internship intrigued Sedera and she plans to further her research experience following graduation. After gaining additional research knowledge Sedera intends to apply to Medical School as an aspiring pediatrician. Throughout the summer and school year, Sedera helps underprivileged youth in her Philadelphia neighborhood with their academics ranging from; reviewing papers, tutoring, and general mentorship. It fills her with great joy when she is able to help others, which is a primary reason for her interest in the medical field. Sedera will be the first person in her family to graduate from college on a full tuition scholarship, and she plans to start her own scholarship fund when she gets established in her medical career.


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