Genetic linkage studies of major depressive disorder have found suggestive evidence across multiple genomic regions with little convergence of findings ¹. Genetic association, including genomewide association studies (GWAS), findings have been similarly disparate ^2–7. These inconsistencies raise the question of whether major depressive disorder encompasses a number of poorly understood subtypes (e.g., depression in smokers). Among smokers seeking cessation treatment, lifetime rates of major depression have been estimated at over 60%⁸. Cigarette smokers with a history of depression tend to report more severe nicotine withdrawal symptoms ^9–11, are more likely to relapse to smoking after a quit attempt⁸, and may be at increased risk for a recurrent episode of depression after smoking cessation¹². Models describing the relationship between symptoms of depression and smoking include examples of shared genetic risk¹³. We carried out genetic linkage analyses of DSM-IV diagnosed major depressive disorder in two samples that are part of the Nicotine Addiction Genetics project^14;15, an international consortium focused on tobacco dependence. We used an affected sibling pair design, in which at least two adult offspring per family reported a history of DSM-IV major depressive disorder, and tested for linkage. Results appear to confirm a genome-wide significant linkage signal at 3p26-3p25, also reported in an independent linkage study of major depressive disorder¹⁶.

For the Australian linkage sample, a multipoint LOD of 4.14 for major depressive disorder was found on chromosome 3 (at 24.9 cM). The highest single-point linkage signal emerged at microsatellite marker D3S1304, with a LOD score of 3.7. The LOD of 4.14 at 3p in this sample met genomewide significance (p = 0.004). A complete report of these single- and multipoint findings, along with marker positions by chromosome, is provided in Table 2 of the data supplement. The addition of 290 SNPs on chromosome 3 narrowed the linkage locus and increased the LOD score to 4.55 (at 25.3 cM) (see Figure 1). For the Finnish major depressive disorder sample, a multipoint LOD score of 2.10 was found on chromosome 20 (at 90.9 cM).

Given that no linkage signals over 1.5 overlapped across both samples, we did not conduct a combined analysis. However, if we were to correct conservatively for testing in both samples by doubling the p value generated from the 1,000 simulations, we would still maintain a genomewide significant p value of 0.008.

Overall, major depressive disorder was associated with a significant genetic linkage peak (a LOD score of 4.14) on chromosome 3 in the Nicotine Addiction Genetics Australian sample, replicating the linkage reported at the same location by Breen et al ¹⁶. These converging findings suggest that the genomic region spanning 3p26-3p25 is an important area for further investigation in genetic research on major depressive disorder. Given the small number of Finnish affected sibling pairs, the lack of confirmation in this particular sample is not unexpected. The genetic variants accounting for this linkage signal have not yet been convincingly identified. Although our highest single-point microsatellite marker (D3S1304 [LOD score =3.7]) lies within the metabotropic glutamate receptor 7 gene (GRM7), subsidiary association analyses within a one-LOD support interval, using GWAS data available in the Australian sample (²⁸), found only nominal association for two SNPs within GRM7 (p < .05). Even our strongest association effect, with was a p value of 0.00014 for rs6765537 (a nonsynonymous SNP within C3or20 at 33.87 cM), did not replicate in the Finnish families, nor did it replicate in the Genetic Association Information Network major depressive disorder sample from the Netherlands^{30, 2}. Thus, while others have found suggestive association between SNPs in GRM7 and Major Depressive Disorder (^7;31), genome-wide significant effects have not been reported. Further, because linkage implicates very broad regions, GRM7 is among many genes that might be hypothesized to explain our signal.

In terms of other linkage findings, one for quantity smoked in samples ascertained for depression has been reported near our chromosome 3 finding for major depressive disorder ³², raising the possibility of common genetic influences across major depressive disorder and smoking-related behavior or of gene-by-environment (i.e., smoking) interaction effects on major depressive disorder.

There are important limitations associated with our results. Our sample of 91 families is small by standards of modern genomic efforts. Thus, we cannot exclude the possibility that our finding is a false positive that coincidentally appears to replicate Breen et al.¹⁶, whose sample is much larger (> 800 families). Additionally, our finding at 3p26-3p25 (highest peak at 24.9 cm) does not align with the meta-analyses results reported by McMahon et al.³³, who suggest that variants located at 3p21.1 (at approximately 70–72 cM) are associated with mood disorders. Our future efforts to localize the genetic variants influencing major depressive disorder will entail confirmatory analyses in other samples and additional genotyping in this region on 3p.