Depression And

Genes

Student name: Rayan Ali Mohammed

Course: Biology
Instructor: Dr. Bushra
Date: 16/June/2020

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 Table of Contents
Introduction …………………………………………….………..………(3)
Causes…………………………….............................................(3)
Quantitative Genetic Studies of Depression…….…………(5)
The Genetic Relationship Between Depression and
Other Disorders………………(6)
Identifying Which Genes Associated with Depression (7)
A- Molecular Genetic Methods: Linkage……………..……(7)
B- Molecular Genetic Methods: Candidate Gene
Associations……………………………………………………….…....(9)
Conclusion………………………………………….…………………..(11)
References……………………………………………….……………..(12)

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 Introduction
Depression (also known as major depression or major depressive disorder) is
a psychiatric disorder that affects mood, behavior, and overall health. It causes
prolonged feelings of sadness, emptiness, or hopelessness, and a loss of interest in
activities that were once enjoyed. People with depression may also have changes in
appetite (leading to overeating or not eating enough), changes in sleeping patterns
(sleeping too much or not being able to sleep), loss of energy, and difficulty
concentrating. Although depression is considered primarily a mental health disorder,
it can also have physical features including headaches, other unexplained aches and
pains, unusually slow or fast movements, and digestive problems. To be diagnosed
with depression, an individual must have signs and symptoms nearly every day for at
least 2 weeks. However, the features of this condition vary widely.

Depression most commonly begins in late adolescence or early adulthood, although it

can appear at any age. If untreated, episodes of depression can last for weeks, months,
or years, and can go away and come back (recur). Affected individuals may have
difficulty functioning in their daily lives, including at school or work. People
with depression have a higher risk of substance abuse problems and dying by suicide
than the general population.

Depression is about twice as common in women as in men, which may be related in

part to hormonal factors.

Causes
Depression is known to run in families, suggesting that genetic factors contribute to
the risk of developing this disease. However, research into the genetics
of depression is in its early stages, and very little is known for certain about the
genetic basis of the disease.

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Studies suggest that variations in many genes, each with a small effect, combine to
increase the risk of developing depression. Determining the genetic risk factors
for depression is challenging for several reasons. It is possible that what is currently
considered to be a single disease called "depression" is actually multiple disorders
with similar signs and symptoms; these disorders could have different genetic risk
factors. The genetic variations related to depression may also be somewhat different
between men and women. Researchers suspect that studies with many more people
will be required to pinpoint the genetic variations that influence the risk of depression.

The genes thought to be associated with depression have diverse functions in the
brain. Some of these genes may control the production (synthesis), transport, and
activity of chemicals called neurotransmitters, which relay chemical signals that allow
nerve cells (neurons) to communicate with one another. Other genes that may
influence the risk of depression are involved in the growth, maturation, and
maintenance of neurons, as well as the ability of the connections between neurons
(synapses) to change and adapt over time in response to experience, a characteristic
known as synaptic plasticity.

Nongenetic (environmental) factors also play critical roles in a person's risk of

developing depression. The disorder can be triggered by substance abuse, certain
medications, or stressful life events (such as divorce or the death of a loved one).
Other risk factors include difficulties in relationships or social isolation,
unemployment, financial problems, and childhood abuse or neglect. Some physical
illnesses, such as cancer, thyroid disease, and chronic pain, are also associated with an
increased risk of developing depression. It is likely that environmental conditions
interact with genetic factors to determine the overall risk of developing this disease

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Quantitative Genetic Studies of Depression
Twin studies can be used to disentangle the relative contribution of genetics, familial
(or shared) and non-shared environmental influences on variability in a trait such as
depression liability, by comparing monozygotic (identical) and dizygotic (non-
identical) twins. Monozygotic twins are genetically identical, and if brought up
together, also share a familial environment. Dizygotic twins are assumed to share
familial environments to the same extent as monozygotic twins; however, as they
share only 50 % of their segregating genes, the differences in within-pair similarity
between monozygotic and dizygotic twins can be used to estimate the heritability of a
trait (the proportion of trait variance that is due to genetic variation between
individuals). Once genetic factors have been considered, any remaining similarities
between twins are due to shared familial environments, whilst within-pair differences
between monozygotic twins can be attributed to nonshared environmental influences.
In a large meta-analysis of twin studies estimated the heritability of depression to be
37 % (95 % CI 31–42 %). Shared environmental factors appeared to have very limited
influence (with a point estimate of 0 %, 95 % CI 0–5 %), whilst 63 % of population
variance in depression liability (95 % CI 58–67 %) could be attributed to non-shared
environmental factors. However, errors in trait measurement are incorporated into
estimates of the influence of non-shared environments, and this may be an important
factor when interpreting the results of twin studies into depression. Kendler
demonstrated that, when lifetime history of depression is assessed with a single
interview, heritability estimates of the trait are around 40 %, but when two
assessments were used to improve the reliability of diagnosis, heritability estimates
rose to approximately 70 %. As many twin studies have relied upon a single
psychiatric assessment in order to determine lifetime history of depression, this may
mean that these studies underestimate the role of genetics in depression. Heritability
estimates for depression also increase when more recurrent forms of the illness are
considered. The pattern of depression in biological and adoptive relatives of adult
adoptees supports the findings of twin studies, also indicating that genes play a key
role in the aetiology of depression, but non-shared environmental influences are also
important.

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 The Genetic Relationship Between
Depression and Other Disorders
Quantitative genetic studies not only give an insight into the relative importance of
genetics in the etiology of depression but can also indicate how the illness might
relate to other disorders. For example, there is a very high degree of symptom overlap
between depression and anxiety, as well as depression and bipolar disorder. There
have been several multivariate quantitative genetic studies examining the relationship
between these disorders, and high genetic overlap between anxiety and depression has
been observed. Indeed, Kendler propose that these two disorders are genetically very
similar; the differences between anxiety and depression are driven by non-shared
environmental factors. Similarly, work in bipolar affective disorder indicates
significant genetic overlap with depression. The relationship between the two
disorders is best explored using a correlated liability model, where patients can be
classified as having depression, mania or both.

Using this model, it has been shown that mania shares both genetic and non-shared
environmental influences with depression.

The genetic correlation between mania and depression was estimated at 0.65 (95 %
CI, 0.58–0.75); however, there are also mania-specific genetic influences (McGuffin
et al. 2003). These observed relationships between depression and other disorders
indicate that the genetic causes of depression are less likely to be unique and suggest
that there may be overlapping causal pathways involved in these disorders.

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 Identifying Which Genes are Associated
with Depression
Whilst quantitative genetic methods are informative as to the relative importance of
genes in depression, this does not tell us which variants are involved in the etiology of
depression. Depression is a complex disorder, where there are likely to be many genes
of small effect which act to influence an individual’s liability to the illness, as well as
number of non-genetic factors. This is indicated by two key factors. Firstly, whilst the
disease is more common amongst relatives, there is no clear pattern of inheritance
between generations. Furthermore, there are many cases of depression where no
family history of the illness is seen. Thus, it is unlikely that a single gene drives the
presence or absence of disease. Secondly, the symptoms of depression can occur
along a spectrum of severity.

In order to identify the genetic variants involved in depression, molecular genetic

methods are required. Two main approaches are used in gene finding, linkage and
association.

Molecular Genetic Methods: Linkage

Linkage techniques aim to identify regions of the genome that contain disease related
genes, by examining the co-segregation of disease and genetic markers in families
containing multiple affected members. If affected relatives share the same allele
(alternative form) of a marker more frequently than expected by chance, then the
genomic region surrounding this marker is likely to contain a genetic variant that is
causally involved in the disorder. Zubenko (2003) published the first genome-wide
linkage study of depression, reporting a linkage signal in the chromosomal region
2q33-34. However, the study was open to a number of methodological criticisms,
including small sample size, and failure to correct for multiple hypothesis testing
(Levinson 2006). Several subsequent studies in depression have looked at genetic
markers across the entire genome and four main genomic regions have been
implicated at chromosomes 3p25-26, 12q22-24, 15q25-26 and 18q21-22, although
findings have not been consistent across reports. In addition to variability in analytic
approaches, studies have also examined a number of different phenotypes, such as
recurrent and early onset MDD (Major depressive disorder), as well as including
genetically related disorders such bipolar disorder and anxiety. Abkevitch (2003)
examined individuals with MDD or bipolar depression and reported a signal within
the 12q22-23.2 region, which became highly significant with fine mapping of the
area. In contrast, (2005) found no evidence of linkage here when looking at those with
MDD or anxiety (excluding those with bipolar depression). This later study did,
however, find suggestive evidence of linkage at 3centr, 7p and 18q21.33-q22.2, the
last of which was a region with suggestive support in the report from Zubenko. Sex-
specific signals were also found in chromosomes 4q and 15q. The signal on

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chromosome 15q received additional supporting evidence from the genetics of
recurrent early onset depression (GenRED) study. In this independent large cohort,
first wave findings reported linkage at 15q25-26 at a genome-wide significance level
(Holmans 2004). The second wave of the study including additional 359 families,
found this signal had attenuated, reaching only suggestive levels of significance
(Holmans 2007). Nonetheless, Levinson. (2007) investigated the region in more
detail, and found that with fine mapping, the signal became highly significant at a
genome-wide level. The authors propose this area contains either one single locus that
increases sibling MDD risk by around 20 %, or multiple loci of smaller effect.
McGuffin (2005) also reported a suggestive signal in this 15q region in the depression
network (DeNT) sample. In this first wave report, suggestive or modest significant
linkage signals were also reported at 1p, 12q and 13q locations. The region in 12q was
adjacent to that implicated by Abkevich (2003). However, as seen in the GenRED
study, in a final report from the DeNT sample (combining wave I and wave II data, to
give a total of 971 affected sibling pairs), these regions showed no strong evidence of
linkage (Breen 2011b). Nonetheless, when the analysis was restricted to patients with
more severe forms of recurrent MDD, a genome-wide significant association in the
3p25-26 region was observed. Although association mapping in the implicated region
in an unrelated case– control did not identify a source for the signal, replication of the
genome-wide signal in a closely overlapping location was reported by Pergadia
(2011) in an independent sample. Middeldorp (2009) did not detect any of these
signals in their Australian and Dutch samples, instead finding suggestive linkage
signals in chromosomes 17, 8p and a novel region of chromosome 2. The authors
noted that the signal in chromosome 8p is in the same region as previously implicated
in personality traits linked to depression (Neuroticism, Fullerton 2003; Harm
avoidance, Cloninger 1998). As can be seen, replication of linkage has been
inconsistent. This may be due to a lack of statistical power to detect signals. It has
been estimated that around 1,000 affected sibling pairs are required to detect a single
locus which causes a 25–30 % MDD risk increase for siblings (Hauser 1996;
Levinson 2003). Only two The Genetic Basis of Depression studies, GenRED and
DeNT, have come close to this sample size and consequently a majority of studies
may have been underpowered to detect true linkage signals.

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 Molecular Genetic Methods: Candidate Gene
Associations
Whilst linkage is better suited to detecting strong genetic effects, association
techniques are more appropriate when looking for multiple genes each with a modest
impact on a complex trait such as depression. Although within family methods can be
used to test for association the simpler and more powerful approach involves
examining genetic polymorphisms in both unrelated patients and disease-free controls
and looking for differences in the frequency of these polymorphisms between the two
groups. If a variant has a small influence on depression liability, then in order to
obtain adequate statistical power to detect this small effect size, larger samples of
cases and controls are required. Genetic association studies can be undertaken either
using a candidate gene approach or in a genome-wide hypothesis free manner.
Candidate gene approaches involve selecting genes and polymorphisms based upon a
prior hypothesis of association with the phenotype of interest. Key pathways that have
been implicated in depression include monoaminergic, neurotrophic and stress
response pathways. Candidate genes related to monoaminergic signaling include the
serotonin transporter (SLC6A4), which is targeted by antidepressants and the
serotonin 2A receptor (HTR2A). Neurotrophic genes include the neuroprotective
protein brain-derived neurotrophic factor (BDNF) and its receptor Trk-B (NTRK2)
whilst corticotrophin-releasing hormone receptor 1 (CRHR1) and FK506 binding
protein 5 (FKBP5) have both been linked to regulation of the hypothalamic pituitary-
adrenal axis stress response pathway. Whilst there is an extensive body of research
looking at the association between candidate genes and depression, sample sizes are
often limited, and findings are frequently inconsistent. Meta analytic approaches are
one method by which to tackle this issue, pulling together the available data from a
number of studies. Lopez-Leon (2008) performed meta-analyses for all
polymorphisms examined in relation to MDD where three or more independent
studies had been performed (listed in Table).

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 Table: Genes included in meta-analysis by Lopez-Leon (2008)
Significant
Gene Variant
Gene name association in meta-
analysis
Angiotensin I-converting enzyme ACE Ins/Del-Intron 16 –

Apolipoprotein E APOE e2/e3/e4 Yes

Brain-derived neurotrophic factor BDNF Val66Met –

Catechol-O-methyltransferase COMT Val158Met –

Dopamine D3 receptor DRD3 Ser9Gly –

Gamma-aminobutyric acid GABRA3 CA repeat-Intron 8 –

receptor, subunit alpha-3

Guanine nucleotide binding GNB3 C825T Yes

protein

Serotonin 1A receptor HTR1A C-1019G –

Serotonin 1B receptor HTR1B G861C –

Serotonin 2A receptor HTR2A A-1438G –

T102C

Serotonin 2C receptor HTR2C Cys23Ser –

Monoamine oxidase A MAOA VNTR-Promoter –

Methylene tetrahydrofolate MTHFR C677T Yes

Reductase
Norepinephrine transporter SLC6A2 T-182C –

Dopamine transporter SLC6A3 40 bp VNTR Yes

3’untranslatedregion

Serotonin transporter SLC6A4 44 bp Ins/Del- Yes

Promoter
VNTR-Intron 2 –
Tryptophan hydroxylase 1 TPH1 A218C –

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 Conclusions
Quantitative genetic methods have established that genetics plays an important role in
determining an individual’s liability to depression, but, critically, genes do not
determine absolutely whether an individual suffers with this complex disease;
environmental factors also play an important role. In attempting to identify which
genetic variants may contribute to depression risk, a range of molecular genetic
methodologies have been employed. Linkage studies attempt to identify regions of the
genome which segregate with disease in affected families and have implicated regions
on chromosomes 3p, 12q, 15q and 18q; however, the interpretation of linkage
findings is more difficult in complex, rather than single-gene, genetic disorders. In
terms of association studies, using current theories of the neurobiology of depression
as a starting point, candidate genes within monoaminergic and stress-response
systems have been investigated. Furthermore, technological developments have
enabled hypothesis-free, systematic analyses and interrogation of common variants
across the entire genome. However, clear associations between genotype and
depression are yet to emerge. Whilst newer approaches such as CNV analysis and
sequencing promise a more thorough consideration of all types of genetic variability,
it appears increasingly likely that if genetic variants do exert a main effect on
depression liability, the size of these effects is small. This fits with evolutionary
theories; if a single variant confers a significant increase in depression risk, given the
reproductive disadvantage associated with the illness, it would be under negative
selection and removed from the population.

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