Neuroendocrine changes of the stress hormone system and REM sleep abnormalities are potential vulnerability markers for depression. Investigating underlying genetics provides new insights into the molecular pathways of these endophenotypes and into the pathophysiology of depression vulnerability. We selected a high-risk linkage and endophenotype approach, i.e., we investigated REM sleep abnormalities (REM density) and altered stress hormone regulation (dex/CRH test) in families with a high prevalence of major depression.

Eleven families were so far included, comprising 82 high risk family members. 32 of them were unaffected, 33 remitted, and 17 suffered from an affective disorder at the time of the investigation. Illumina Infinium Whole Genome genotyping with 100k bead chips was performed. Variance component (VC), and a quantitative trait linkage analysis (QTL) on polysomnographic (REM density) and neuroendocrine vulnerability markers (dex/CRH test) were applied.

Linkage analysis (VC, QTL) revealed suggestive linkage (LOD score > 2) for altered REM density at loci of the chromosomes 2, 4, 8 and X. The linkage results on chromosomes 2 and X correspond to previous findings. No results were obtained with a classical diagnosis based linkage approach.

The use of quantitative vulnerability markers in a high risk family study and a SNP based whole genome approach revealed a number of loci with suggestive linkage, that were not detectable with the classical linkage approach. Our findings suggest the suitability of investigating vulnerability marker in combination with a SNP based whole genome approach in complex disorders like depression.