MAY 31, 2020

“Depression is being colorblind and constantly told how colorful the world is”.

(Atticus)

GENETICS OF DEPRESSION
MOLECULAR BIOLOGY ASSIGNMENT

SYED MUHAMMAD ZAKI HAIDER (BSBT025F18)

SUBMITTED TO: DR. MOAZZAM ALI
Institute of Biotechnology and Biochemistry, University of the Punjab
 GENETICS OF DEPRESSION 05/31/2020

DEPRESSION, A MOOD DISORDER:

Mood disorders are used to describe a portion of neuropsychiatric diseases resulting from abruptly
changing and often long lasting disturbances in a person’s mood due to pathological disturbances[1].
Depression, bipolar disorder and schizoaffective disorder are most common in this portion[1]. Major
depressive disorder or MDD (henceforth, depression) is undoubtedly a commonly prevailing mental
disorder[2] and a global health issue both on individual and socioeconomic level [3]. Afflicting adolescents
and young adults (between ages 15-39 years) as a third major cause of disability and second one for
middle aged people globally[3], depression devours of precious lives by suicide. In most Western
countries, MDD has a 1-year prevalence of ~5% and a lifetime prevalence of ~15%[4] and is characterized
by a low mood, guilt and decreased enjoyment along with other additional indications including reduced
concentration, depleted self-esteem, weight loss, disturbed appetite and sleep[5]. Depression is a natural
human emotion, but in MDD, this mood prevails for longer durations.

COMPLEXITY OF THE DISORDER:

MDD is proved to be clinically heterogenous because the severity, treatment procedures and duration,
outcomes, medication, drug response and other clinical and pathological factors varies greatly among
patients, which also refers to causal heterogeneity, making it a complex disorder[5]. Genetic and
environmental factors like chronic stress and early-life adverse events, have been identified as disease
contributors for MDD[1]. Then the psychiatric comorbidities are also a cause of heterogeneity in
depression as pure depression is a rare exception, and is usually associated with some other psychiatric
conditions[6]. In addition, phenotypic heterogeneity is augmented by co-occurring psychiatric
problems[4], due to which genetic variants seem to influence a portion of depression only.

GENETICS AND GWAS STUDIES ON DEPRESSION:

Heritability of depression is approximately 37% according to twin heritability studies[7], upper and lower
limits mainly ranging from 31%-42%[8]. This amount of twin heritability, demands massive amounts of
samples for efficient gene identification. Identification of the gene loci and their variants has been a vexing
task as depression is a polygenic disorder (i.e phenotype is not associated with effect of one gene but with
multiple non epistatic genes)[7] and highly heterogenous in nature[6]. GWAS (genome wide association
studies) refers to an approach used in genetics research to link specific genetic variations with particular
diseases, involving scanning the genomes from many different people and looking for genetic markers
that can predict the presence of disease. Once the region in genome associated with the disease is
detected, it becomes easier to study its role in the disease and working out for a treatment strategy.
GWAS studies have been for depression as well, using the tests and experiments to spot differences in
allele frequencies between disease and control groups at millions of common single nucleotide
polymorphisms (SNPs) across the genome[7]. Identifying risk loci and GWAS studies have been challenging
due to the heterogenetic nature of depression, higher life time prevalence (approx. 15%) and modest
heritability[7].the most recent GWAS studies including data from PGC (psychiatric genomics consortium),

SYED MUHAMMAD ZAKI HAIDER (BSBT025F18) 1

 GENETICS OF DEPRESSION 05/31/2020

the personal genetics company 23andme, DeCODE and the UK biobank identified 102 independent
genetic variants that may increase risk for depression[9].

CONVERGE consortium:
The CONVERGE (China, Oxford and Virginia Commonwealth University Experimental Research on Genetic
Epidemiology) consortium conducted GWAS study, aiming on unraveling a more homogenous sample by
restricting the phenotype to recurrent severe depression in women[7]. Low-coverage sequencing of 5303
Han Chinese MDD cases and 5337 controls revealed association of two SNPs on chromosome 10: one
near the SIRT1 gene and the other in an intron of LHPP[7], thus focusing on a homogenous phenotype
where the genetic contribution is larger and effects are easier to find.

CHARGE Consortium and PGC:

Results from CHARGE consortium GWAS on depression symptoms and PGC GWAS on MDD were
combined, using an approach of forming a spectrum of depression ranging from minor depression to
higher thresholds (MDD, mild, severe)[7]. Symptom evaluation was done in individuals above 40 years of
age using validated questionnaires (mostly using the Center for Epidemiological Studies Depression Scale
CES-D),which focused on depressive symptoms in the previous weeks rather than lifetime[7]. The meta-
analysis in this continuum approach identified a one genome-wide significant SNP, located in an intron of
FHIT, which is expressed in several brain regions and encodes a tumor suppressor protein also involved
in oxidative stress and the circadian clock[7]. A strong genetic correlation (rG = 0.86, s.e. = 0.05) between
broader self-declared definitions of depression and clinically diagnosed major depressive disorder (MDD)
was observed within a hospital setting[9]. Here the SNP heritability (for a broad depression phenotype)
was found to be greater than that of depression symptoms and MDD separately (as studied above)[7].

Neurotrophic factors:
A role for the loss of neuroprotection and distorted neurotrophic factor signaling in depression has been
supported by various findings in both humans and animal models[1]. Neuroprotective neurotrophin brain-
derived neurotrophic factor (BDNF) reduces neurotoxicity and neuroinflammation which cause
depression. Its genetic structure is such that it is highly susceptible to epigenetic regulations, having 11
exons and 9 different promoters, it is highly regulated at the post-transcriptional level, including
alternative splice and polyadenylation sites, influencing its subcellular distribution and function[1]. A
prominent genetic variation of BDNF Val66Met SNP leading to a valine-to-methionine substitution in
proBDNF that affects processing and sorting was shown to alter activity-induced secretion of BDNF and
memory performance in humans[1]. Mutations in the gene coding for the neurotrophin receptors TrkB
and p7592, have been associated with depression, but a recent metaanalysis studying polymorphisms in
BDNF, NTRK2 (gene coding for TrkB), and NGFR (gene coding for p75) only found a strong correlation for
the Val66Met polymorphism of BDNF due to limited sample sizes of samples for GWAS studies[1]. DNA
methylation profiles of CpG I of the BDNF gene may also be a valuable MDD diagnostic biomarker[10].

SYED MUHAMMAD ZAKI HAIDER (BSBT025F18) 2

 GENETICS OF DEPRESSION 05/31/2020

Serotonin and depression:

Serotonin (5 hydroxy-tryptamine or 5HT) is a neurotransmitter that plays an important role in mood
regulation and response to stress. Alterations in gene expressions that regulate the biological effects of
serotonin in the brain could alter serotonergic signaling, and thus might ultimately alter behaviors where
5-HT has been implicated[11]. Tryptophan hydroxylase (TPH) is the rate-limiting enzyme for the synthesis
of 5-HT from L-tryptophan, and is encoded by 2 genes: TPH1 and TPH2[11]. A more limited number of
genetic association studies of the Tph2 gene have been reported. In 2005, a loss of function SNP (G1463A)
in the Tph2 gene which replaces the arginine 441 with histidine was identified and reported to occur more
frequently in subjects with unipolar major depression compared to controls[11]. As far as TPH1 gene is
concerned, 218A/C polymorphism, along with other polymorphism and a microsatellite on TPH1 is
claimed to be associated with depression[11]. A polymorphism in the promotor region (5-HTTLPR) of the
serotonin transporter gene ( SLC6A4 ) accounts for up to 10% variance of amygdala activation[8]. In
insertion/deletion polymorphism in 5-HTTLPR forming S (short) and L (long) alleles, S allele is known to be
associated with MDD when combined with other genetic or environmental risk factors[11].

CONSUMER GENOMICS AND ONLINE DNA TESTING:

From inception of human genome project (HGP) to present consumer genomics, genetics and
biotechnology has come a long way. Sending a sample of our spit in the mail and pay to see how our
unique genetic code influences our life—from sports to certain diets to skin cream to a preference for fine
wines, even to dating is sure nothing less than a miracle[12]. Following the completion of HGP, almost
a100 companies emerged offering online DNA tests, for instance 23andme, deCODEme, Mycellf, Knome
etc. mostly using 1st person personal pronouns as their signatures names[13]. Companies attract
customers via promoting consumer genomics with the concept of genetic essentialism (the view that our
genomes do intrinsically define our personal identities, as secular substitutes for the “soul”)[13]. Despite
latest behemoth sequencing technologies and techniques, the accuracy is still under question.

Two questions arise when it comes to these online companies: 1) has the sequencing been done correctly?
2) how was the genetic sequencing data interpreted? Predominantly it seems okay to assume that data is
correct, but there have been blunders at times too. One recent analysis found 40 percent of variants
associated with specific diseases from “direct to consumer” (DTC) genetic tests were shown to be false
positives when the raw data was reanalyzed[12].Then variation in company’s database can give rise to
discrepancies as well . Almost every DTC genetic test does not sequence your entire genome, but looks at
positions in your DNA that are known to be of interest[12]. In case the information is errorless,
interpretation is where things get foggy. Because heterogenic cases like height, depression, diet, exercise,
weight management, mental conditions etc. increase genetic variants for GWAS studies as mentioned
earlier. Thus, it turns out that genetic variants collectively share the polygenic condition which is also
being affected by environmental factors, not genetics alone. Genetics is a probabilistic science, and there
are no genes “for” anything in particular[12].

SYED MUHAMMAD ZAKI HAIDER (BSBT025F18) 3

 GENETICS OF DEPRESSION 05/31/2020

MDD is a genetically complex disease with 30-40% heritable with environmental factors contributing to
its risk[14]. To reach statistical power and accuracy in GWAS studies, larger cohorts are needed[14]. Now,
consumer genomic companies like 23andme can provide large scale data sets on depression via their large
consumer pool, saving money and time in going for larger cohorts. And there are also some critiques
saying that self-reported cases can cause inaccuracy (for they may not relate to MDD), but as depression
can co-occur with psychiatric comorbidities, so self-reported data may not cause inaccuracy. In a nutshell,
consumer genomics, despite its uncertainties in accuracy, may still pave way to infer genetic markers for
complex diseases. Could genomic profiling and genetic testing play legitimate parts in an individual’s
process of self-identification? Possibly, but only if its purveyors can give up the essentialistic rhetoric in
which it is cloaked, and treat the science with the modesty it still deserves[13].

CONCLUSION:
Depression is a complex disorder, with genetical effects intertwined with environmental factors and
psychiatric comorbidities. GWAS studies conducted by various scientific communities and consortiums
has pointed out genetic variants. Data from DTC companies despite their critiques on methodologies and
accuracy has also helped in this regard. The journey of unraveling the secrets of DNA linkage with our daily
lives, ancestry and diseases like depression is far from over...

REFERENCES:
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[2] E. M. Byrne et al., “The Australian Genetics of Depression Study: Study Description and Sample
Characteristics,” Genetics, preprint, May 2019. doi: 10.1101/626762.
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[9] D. M. Howard et al., “Genome-wide meta-analysis of depression identifies 102 independent variants
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[10] M. Fuchikami et al., “DNA Methylation Profiles of the Brain-Derived Neurotrophic Factor (BDNF)
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[12] A. Rutherford, “How Accurate Are Online DNA Tests?,” Scientific American.
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[14] J. Abbasi, “23andMe, Big Data, and the Genetics of Depression,” JAMA, vol. 317, no. 1, pp. 14–16,
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