FAMILY HISTORY AS AN IMPORTANT FACTOR
FOR STRATIFYING PARTICIPANTS IN GENETIC
STUDIES OF MAJOR DEPRESSION
Zalar B, Blatnik A, Maver A, Klemenc-Ketiš Z, Peterlin B
*Corresponding Author: Professor Borut Peterlin, Clinical Institute of Medical Genetics, Division of Obstetrics and Gynecology,
University Medical Center Ljubljana, Šlajmerjeva 3, 1000 Ljubljana, Slovenia. Tel: +386-1-5401-137. E-mail:
borut.peterlin@guest.arnes.si
page: 5
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DISCUSSION
The polymorphic variants included in our analyses
have all been thoroughly studied in connection to psychiatric
disease. The common Val158Met polymorphism
in the COMT gene (due to a G>A transition) has been
the subject of several association studies performed in
different populations and often with conflicting results.
Whereas some studies have detected an association between
the low activity methionine allele and depression,
others have yielded opposite, or, more often, negative
results [27,28]. The 5-HTTLPR promoter repeat variant
of the SLC6A4 gene is perhaps the most widely studied of
all the common variants that were investigated in MDD
using the candidate gene approach. Two variants are usually
reported in humans, namely the short (S) and long (L) allele, although the repeat region is complex and can
be subdivided into several allelic variants. The S allele
has been repeatedly linked to depression or to the personality
traits predisposing to depression, most famously
in the setting of gene-environment interaction [29,30].
Even though some meta-analyses appear to confirm its
role in the etiology of MDD, there is poor replication
between similarly designed studies [31]. The PCLO gene
was first identified as a candidate MDD gene in a GWAS
study in which no findings of genome-wide significance
were detected, but a suggestive result was obtained for the
rs2522833 PCLO polymorphism [32]. Again, the attempts
to replicate these results have not been completely successful.
However, some studies have linked the C allele
to an increased vulnerability to depression, both directly
and through its influence on those personality traits which
increase the risk of MDD [33,34].
Our study conducted in Slovene MDD patients found
no evidence of a link between the presence of putative high
risk alleles in COMT, PCLO or SLC6A4 and the likelihood
of either having depression or having a family history of
depressive disorder. On the contrary, our results for the
PCLO rs2522833 polymorphism show that homozygosity
for the presumed high risk C allele is less common in
patients with a positive family history for a depressive
disorder compared to those with no family history of depression
or compared to the controls. The small number of
participants in this study prohibits any definite conclusions
to be drawn from these results as there is a possibility that
the association we have detected has arisen due to chance.
Nevertheless, these findings would appear to suggest that a
polymorphism previously associated with both MDD and
endophenotypes seen as predisposing factors for depression
is not a contributing factor for MDD in families with
several affected members. It therefore seems possible that
the genetic factors involved in the etiology of depression
in families with several affected family members differ
from those involved in sporadic cases of depression. Rare
variants of great affect would appear to be the most likely
candidates, especially in families with a greater number
of affected members, a recognizably Mendelian pattern of
inheritance, and early disease onset. Such patients would
therefore seem more appropriate candidates for next generation
sequencing (NGS)-based techniques of investigation
rather than SNP genotyping.
The genetic architecture of the most common diseases,
including depression, is likely to be complex, with
rare cases of clear monogenic inheritance and a somewhat greater number of familial cases associated with
oligogenic inheritance. In most patients with common
diseases, however, a great number of common risk variants
is thought to contribute to the likelihood of developing
the disease. Our findings raise an interesting question
for those searching for such common variants associated
with depression: if the failure of past studies is due to
the heterogeneous nature of genetic causes involved in
different patients, could excluding patients with similarly
affected relatives increase the chance of positive findings
in sporadic cases? Although no statistically significant
differences were discovered when comparing our patients
with no family history of depression to the controls, there
was a trend towards a greater S allele frequency for the
SLC6A4 5-HTTLPR variant and a trend towards a greater
C allele frequency and CC homozygosity for the PCLO
rs2522833 polymorphism in these patients; both variants
have also been linked to MDD in the past. This trend was
undetectable when all depressed patients were compared
to the controls, suggesting that the admixture of familial
cases changed the genotype and allele distributions. Our
results show that focusing on sporadic cases of depression
might provide a more homogenous sample for future association
studies. The number of participants included in
GWAS would no longer have to be prohibitively large and
such studies might stand a better chance of detecting variants
with a small contribution to the overall disease risk.
Some of the previous studies which subdivided the
participants according to their family history only enquired
about first-degree relatives [28]. As there is evidence that
the presence of MDD in second-degree relatives can influence
the risk of developing depression, we would suggest
that one should also enquire about the disease status in
second- and perhaps even third-degree relatives [21].
One of the limitations of our study is the small number
of participants. The study was therefore underpowered
to detect significant associations. Furthermore, as all of
the data concerning the family history of our participants
was collected by patient recall, some of it was bound to
be unreliable and incomplete.
Major depressive disorder is an important health problem
worldwide and studying its genetic etiology might one
day lead to better diagnostic and treatment options for those
affected [35,36]. However, no genetic variants identified so far seem to offer hope of a clinically useful screening
test for the near future [37]. As researchers try out different
approaches to genetic studies of depression, stratifying
patients into subgroups when performing a GWAS
becomes increasingly important [38,0]. We would argue
that enquiring about the patients’ extended family history
of this disease could prove a simple and effective way of
differentiating patients with different genetic etiologies.
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