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
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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 patientsí extended family history of this disease could prove a simple and effective way of differentiating patients with different genetic etiologies.



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