AbstractThe clinical manifestation of depression comprises a variety of symptoms, including early morning awakenings and fatigue, features also indicating disturbed sleep. The presence or absence of these symptoms may reflect differences in neurobiological processes leading to prolonged depression. Several neurobiological mechanisms have been indicated in the induction of depression, including disturbances in serotonergic and glutamatergic neurotransmission and in the action of the hypothalamic–pituitary–adrenal (HPA) axis. The same transmitters have also been linked to sleep regulation. We hypothesized that depression without simultaneous symptoms of disturbed sleep would partly have a different genetic background than depression with symptoms of disturbed sleep. We tested this hypothesis using a systematic population‐based association study of 14 candidate genes related to depression and disturbed sleep. Association of genetic variants with either depression alone, depression with early morning awakenings, or depression with fatigue was investigated using permutation‐based allelic association analysis of a sample of 1,654 adults recruited from Finland's population‐based program. The major findings were associations of TPH2 (rs12229394) with depression accompanied by fatigue in women and CREB1 (rs11904814) with depression alone in men. We also found suggestive associations in women for GAD1, GRIA3, and BDNF with depression accompanied by fatigue, and for CRHR1 with depression accompanied by early morning awakenings. The results indicate sex‐dependent and symptom‐specific differences in the genetic background of depression. These differences may partially explain the broad spectrum of depressive symptoms, and their systematic monitoring could potentially be used for diagnostic purposes. © 2009 Wiley‐Liss, Inc.