Genomics: Insight

Major Depressive Disorder: A Health Crisis

Recent surveys estimate that 10-15% of general populations suffer from major depressive disorder (MDD).4 Major depressive disorder, a common and complex mood disorder, is one of the leading causes of death in the developed world.3 In the United States, over 5% of adults are affected by recurrent MDD, amounting to a societal cost of around $43 billion (Greenberg et al).1 The familial, societal, and economic tolls of major depressive disorder cannot be stressed enough. Major depressive disorder continues to plague millions of teenagers and adults due to the unique combination of environmental and genetic factors that contribute to its emergence. In recent years, scientists have made a concerted effort to determine the specific gene loci involved in the genetic component of MDD. Although environmental factors (i.e. childhood trauma, serious medical conditions, substance abuse, significant loss, etc.) often trigger the initial appearance of the disease, genetic predisposition to depression often contributes to the severity and onset of the depression. Estimates regard genetic factors as accounting for 30-40%1 of the contributors to the development of depression. Thus, major depressive disorder results from genetic predisposition and environmental influences.

Thus, major depressive disorder results from genetic predisposition and environmental influences.

Depression Loci on the SLC6A4 Gene

To examine the role of genes on MDD, scientists have begun researching the specific gene loci that contribute an individual’s predisposition to MDD. One study conducted by the Department of Pharmacodynamics at Semmelweis University in Budapest determined one such loci as the SLC6A4 gene. In humans, the SLC6A4 gene codes for the serotonin transporter protein responsible for the regulation of mood. The 5-HTTLPR polymorphism (a variation of DNA base pairs in the genome) on this serotonin transporter gene has been associated with neuroticism and other anxiety related traits, both which increase an individual’s risk for depression (Bagdy et al.). Additionally, the study produced clinical evidence showing a marked association between the polymorphism and stress-induced reactivity, meaning a decreased ability to respond to stressors with composure. In individuals with the 5-HTTLPR polymorphism, the amygdala (the part of the brain responsible for fear response) has a faster and heightened response. In his book The Body Keeps the Score, Bessel Van Der Kolk, M.D. describes the amygdala as the brain’s “smoke detector” and discusses the role trauma and depression play in complicating the amygdala's ability to discern whether a situation is dangerous or safe.8 The contribution of the 5-HTTLPR polymorphism in complicating the body’s stress response exacerbates the brain’s sensitivity to possible triggers, entrapping patients in a cycle of relived trauma. Not only is this heightened stress response a symptom of depression, the genetic component of amygdala hyperactivity can act as a precursor to MDD. The results of the Semmelweis study corroborate the findings of a longitudinal study of the same polymorphism from 2003, which was later confirmed by a meta-analysis in 2011. Genetic factors alone do not account for the expression of MDD genes in patients; indeed, environmental factors such as provoking early life events, seasonal changes, interpersonal relationships trigger the manifestation of the disease (Bagdy et al). Similarly, individuals with genetic predisposition to MDD will not necessarily have the disease during their lifetime given the absence of environmental strain. Given the vast array of responses to everyday stressors, determining the exact ratio of environmental to genetic factors contributing to the development of MDD in an individual is near-impossible. The study presents a model suggesting that genetic factors determine an individual’s sensitivity towards trauma and stressors, such as childhood trauma, loss, and health changes. 

Genetic Predisposition to MDD on the 12th Chromosome

The genetic component of major depressive disorder was further clarified in a study conducted by Abkevich et al. that confirmed the presence of genes involved in MDD on the 12th chromosome. The results, while sex-specific, support the overall conclusion that major depressive disorder hails from a combination of genetic predisposition and environmental factors. The study collected data from 1,890 individuals, 784 of whom are affected with recurrent MDD (238 males and 546 females), 161 with a single episode of MDD (48 males and 113 females), and 162 with BPD (borderline personality disorder) (62 males and 100 females). Using a linkage analysis (a form of “gene-hunting” that locates a disease causing gene) on the 1,357 genotype samples, the scientists categorize their results using the LOD score. The National Library of Medicine defines the LOD score as a statistical estimate of the power and probability of a specific linkage, or the close association of genes on a particular chromosome.7 The score serves as an estimate of whether two particular genes are likely to be located near one another and subsequently inherited. The results indicated “highly significant” evidence for a gene in the 12q22-q23.2 chromosomal region that predisposes individuals to major depressive disorder (Abkevich et al.). 86% of males affected by MDD in the study reported having the haplotype associated with MDD on the 12q22-q23.2 chromosomal region (Abkevich et al.)1 The series of inherited polymorphisms correlates strongly with the development of depression in males. In females, the results were less conclusive, with only 39% of affected females sharing the haplotype. The study posits one of the first conclusive data sets providing evidence for a male-specific MDD gene. The results, while sex-specific, support the overall conclusion that major depressive disorder hails from a combination of genetic predisposition and environmental factors. The presence of the MDD gene within individuals without depression explains the environmental reaction or trigger needed to cause the disease. Because individuals can have polymorphisms correlated with depression without having symptoms of MDD, the interaction is clarified. 

Low Coverage Sequencing Confirms Presence of Depression Gene on Chromosome 10

Consistent with the data from the aforementioned studies, dataset 3 confirms the correlation between genomics and MDD using low coverage genome sequencing, a method of gene identification that uses many samples and computational statistics to decode the genome. The study, published in July 2015, sequenced the DNA of 5,303 Chinese women with recurrent MDD and identified two genome-wide significant loci contributing to risk of MDD. The loci identified are on chromosome 10: one near the SIRT1 gene and the other on an intron of the LHPP gene.5 The study, which attributes much of its success to the homogeneity of its patients, begins by discussing the contribution of environmental factors in the development and severity of MDD. The study identifies the countless iterations and risk factors for depression, underscoring the difficulty in conclusively determining the loci responsible for MDD. After acknowledging the existence of cases of MDD which hail solely from environmental factors, the study demonstrates the variability in the significance of genetics in the development and severity of MDD. Unlike the previous datasets, the DNA genotyped in this study is from patients diagnosed with major depressive disorder. The dataset establishes two MDD loci within a  group of women from the same geographical area who already suffer from the disease. Determining the genetic interaction with environmental factors requires careful examination of possible stressors. The study identifies a gene contributing to the expression of MDD in females. Regardless of the broader environmental-genomic interactions causing MDD, the study was able to produce evidence of single nucleotide polymorphisms (SNPs) correlating to the presence of MDD. Both loci identified (at the SIRT1 gene and the LHPP gene) have a SNP that is replicated across the patients suffering from MDD. 

Drawing Conclusions and Moving Forward

Although scientific attention towards the genomics of depression has increased in the past few decades, a full, unobstructed view of the etiology of MDD eludes us. With a comprehensive understanding of the genomics and environmental factors influencing depression, doctors can identify children most at risk for developing MDD. Moreover, given an understanding of a patient’s personal history and genomics, doctors can pinpoint high-risk patients. While it’s unclear if genomics studies will aid in curing depression in individuals, continued research in this area could inform preventative measures that will lessen the numbers of people suffering from depression. The societal strain caused by MDD cannot be overstated: depression accounts for over 30% of suicide mortalities, which total around 800,000 per year.2 MDD has consistently been tied to increased absenteeism, poverty rates, and unemployment, which total societal costs of $36.6 billion per year in the United States (Bachmann). In a 2009 study of adolescents at a public high school, 18.4% of the population had evidence of suffering from depression.6 Decoding the genetic and environmental factors influencing susceptibility to depression enables doctors to identify and protect at-risk individuals from a young age. Our nation faces a national health crisis, and science presents the tools for a solution. 

Although scientific attention towards the genomics of depression has increased in the past few decades, a full, unobstructed view of the etiology of MDD eludes us.

References

1. Abkevich, Victor, et al. “Predisposition Locus for Major Depression at Chromosome 12q22-12q23.2.” The American Journal of Human Genetics, vol. 73, no. 6, 1 Dec. 2003, pp. 1271–1281, www.sciencedirect.com/science/article/pii/S0002929707639809, 10.1086/379978. Accessed 14 May 2020. 
2. Bachmann, Silke. “Epidemiology of Suicide and the Psychiatric Perspective.” International Journal of Environmental Research and Public Health, vol. 15, no. 7, 6 July 2018, p. 1425, www.mdpi.com/1660-4601/15/7/1425, 10.3390/ijerph15071425. 
3. Bagdy, Gyorgy, et al. “A New Clinical Evidence-Based Gene-Environment Interaction Model of Depression.” Neuropsychopharmacol Hung, vol. 14, no. 4, 2012, pp. 213–220, mppt.hu/magazin/pdf/xiv-evfolyam-4-szam/bagdy_web.pdf, 10.5706/nph201212001). Accessed 7 Feb. 2022. 
4. Briley, Mike, and Jean-Pierre Lépine. “The Increasing Burden of Depression.” Neuropsychiatric Disease and Treatment, May 2011, p. 3, 10.2147/ndt.s19617. 
5. CONVERGE consortium. “Sparse Whole-Genome Sequencing Identifies Two Loci for Major Depressive Disorder.” Nature, vol. 523, no. 7562, July 2015, pp. 588–591, www.nature.com/articles/nature14659, 10.1038/nature14659. 
6. Goyal, Sunil, et al. “Study of Prevalence of Depression in Adolescent Students of a Public School.” Industrial Psychiatry Journal, vol. 18, no. 1, 2009, p. 43, www.ncbi.nlm.nih.gov/pmc/articles/PMC3016699/, 10.4103/0972-6748.57859. Accessed 16 June 2019. 
7. Rice, J. P., et al. “The Lod Score Method.” Advances in Genetics, vol. 42, 2001, pp. 99–113, pubmed.ncbi.nlm.nih.gov/11037316/, 10.1016/s0065-2660(01)42017-7. Accessed 8 Feb. 2022. 
8. van der Kolk, Bessel. The Body Keeps the Score: Mind, Brain and Body in the Transformation of Trauma. London, Penguin Books, 2014, pp. 51–73. (8)