Combined Linkage and Association Analyses of the 124-bp Allele of Marker D2S2944 with Anxiety, Depression, Neuroticism and Major Depression

Abstract

A central issue in psychiatric genetics is whether positive findings replicate. Zubenko et al. (2002b, Mol. Psychiatry 7:460-467) reported an association of the 124-bp allele of D2S2944 with recurrent early-onset major depression for females. We tested for association of this allele to continuous measures of anxiety, depression and neuroticism in a Dutch sample of 347 males and 448 females, and to DSM-IV major depression in a subsample of 210 males and 295 females. The association of the 124-bp allele to depression in females was not replicated, but there were significant associations (not significant after correction for multiple testing) with anxiety and anxious depression in males. However, the association occurred in the absence of evidence for linkage in this region on chromosome 2.

Linkage scan for quantitative traits identifies new regions of interest for substance dependence in the Collaborative Study on the Genetics of Alcoholism (COGA) sample

“…Work by Zubenko and colleagues has also suggested a role of CREB1 on mood disorders; this lies 20 cM centromeric to our linkage peak (Zubenko et al, 2003a). These authors have also identified a sex-specific association between the 124bp repeat allele of D2S944 and recurrent, early-onset major depression and with anxious depression in an independent U.S. and Dutch sample (Beem et al, 2006;Philibert et al, 2003;Zubenko et al, 2002). Due to the high level of comorbidity between alcohol and drug dependence and major depression, and as indexed by a high LOD score of 3.49 for comorbid alcoholism and major depression in prior linkage analyses using COGA data (Nurnberger, Jr. et al, 2001), this region on chromosome 2 may be tapping into a region of susceptibility for both disorders.…”

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“…In addition, past studies have suggested for substantial overlap of the genetic factors influencing liability to a wide range of internalizing disorders (Hettema et al, 2006). Comparing our results to those from linkage scans of suicide attempts (Willour et al, 2007), neuroticism (Beem et al, 2006), bipolar disorder (Marcheco-Teruel et al, 2006), panic disorder (Gelernter et al, 2001), and anorexia nervosa (Devlin et al, 2002) indicates some overlap with our reported regions.…”

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“…Philibert et al 2003 confirmed the selective association of the D2S2944 124 bp allele among women with RE‐MDD, while Langbehn et al 2006 reported an association of this allele with MDD complicated by alcohol abuse/dependence and/or antisocial personality disorder. Beem et al 2006, following up a finding of suggestive linkage (LOD∼1.5) of neuroticism to the region containing CREB1 , reported a nominally significant ( P = 0.04) sex‐specific association for anxiety in males that did not survive correction for multiple testing.…”