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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INTRODUCTION

Depression is a major cause of disease and disability. It consists of several symptoms, such as depressed mood, loss of interest or pleasure, decreased energy, feelings of guilt or low self-worth, disturbed sleep or appetite, and poor concentration. One-third of all people seeking psychiatric help are depressed; in more economically developed countries, one in five people will be depressed at least once in his/her life, and in poorer ones, this ratio is much worse. Major depression usually strikes without a a discernible triggering event. This can be confusing and frustrating for both the person affected and his/her surroundings. People expect their illnesses to have clear causes, but many serious diseases, such as cancer, usually have none. Major depression is indeed a serious disease that often causes despair and hopelessness so profound that the person loses all interest in life, becomes incapable of feeling pleasure, and may be unable to get out of bed or eat for days at a time. The total annual cost of depression in Europe is about 253 Euro per inhabitant [1]. Genetic susceptibility to major depressive disorder (MDD) is a field of study that has baffled many researchers; while it has shown great promise, it has actually yielded very few tangible results. Major depressive disorder has long been known to be moderately heritable. Twin studies have repeatedly shown the heritability of major depression to be about 37.0-38.0% [2,3]. Different approaches to studying the genetics of MDD have so far been consistent only in their inconsistency; linkage studies, candidate gene approaches, studies of gene-environment interaction, and more recent genome-wide association studies (GWAS) have failed to give significant or reproducible results [4,5]. Genome-wide association studies in particular have shattered hopes of finding significant common risk variants. Previously detected associations with genes such as those in the monoamine synthesis pathway have not been replicated in GWAS and no new, clear-cut candidates significantly associated with MDD have been discovered [6,7]. These results are in stark contrast to results for other complex diseases such as diabetes, Crohnís disease, and rheumatoid arthritis, where GWAS have been considerably more successful in identifying potentially interesting loci [8-10]. Researchers are now trying to find novel approaches in their quest for the missing heritability of MDD [11]. Many reviewers agree that the aforementioned failure of GWAS could be due to the fact they were underpowered [12]. A great number of different loci might play a role in determining a personís predisposition to develop MDD, but if that is indeed the case, the effect of each contributing variant could be exceedingly small. It has been estimated that sample sizes in excess of 50,000 might be needed for variants with genome-wide significance to be discovered [11]. A possible approach that might enable researchers to lower the necessary number of participants in future studies would be to concentrate on the various subtypes of depressive disorders, as there is evidence MDD is a genetically heterogeneous disorder [13]. Depression is more heritable in women and is associated with different genetic variants in both sexes [14,15]. Studying patients with early onset disease, choosing patients with more severe forms of the disease and a higher recurrence rate, as well as focusing on various clinical subtypes, could also help distinguish between different genetic influences. It is also important to acknowledge that there is a considerable overlap between MDD and other psychiatric disorders such as bipolar disorder and generalized anxiety disorder (GAD). Some studies show that the genetic factors underlying both MDD and GAD are essentially the same [16-19]. Another approach to subdividing patients with MDD that has occasionally been used in the past, is to enquire about their family history of depression. A positive family history is the most important risk factor for developing a depressive disorder and is often found in patients with more severe and recurrent disease and an earlier age of onset [20,21]. Linkage studies performed in families with several affected members have shown that many different loci could be associated with the familial form of the disease [22,23]. Estimates of single nucleotide polymorphism (SNP) heritability performed so far seem to indicate that more than 50.0% of MDD heritability is due to common variants [24], but the possibility that rare variants of great effect also account for some MDD heritability cannot be excluded. It is therefore possible that both combinations of common risk variants and specific rare variants are at play in familial cases. Based on these findings, our study aimed to explore the connection between the family history of depression and the presence of common genetic risk factors for MDD. First, we set out to determine the allele and genotype distributions for the extensively studied SLC6A4, COMT and PCLO polymorphisms in Slovene patients with MDD and to compare them to healthy controls. We then tried to detect any differences in the prevalence of these putative genetic risk variants in MDD patients with a positive family history of depressive disorder compared to sporadic cases with no affected relatives.



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