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 Netherlands30, 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.