ABSTRACT
Major depressive disorder (MDD) is a common, clinically heterogeneous disorder often found comorbid with other disorders. We studied recurrent, early-onset MDD (MDD-RE) and anxiety disorders in combination to define powerful phenotypes for genetic study. We used 87 large, extended Utah pedigrees to investigate linkage to 3 phenotypes: "MDD-RE;" "MDD-RE or anxiety;" and "MDD-RE and anxiety;" where in the latter definition the disorders must appear comorbid within an individual. Pedigrees ranged in size from 2 to 6 generations and contained 3 to 42 individuals affected with MDD or anxiety (718 total). In primary analyses, we identified three regions with at least suggestive genome-wide evidence for linkage on chromosomes 3centr, 7p, and 18q. Both 7p and 18q are replication findings for related phenotypes. The best linkage evidence was for a novel locus at 3p12.3-q12.3 (LOD = 3.88, "MDD-RE or anxiety") and 18q21.33-q22.2 (LOD = 3.75, "MDD-RE and anxiety"), a well-established susceptibility locus for bipolar disorder. In our secondary sex-specific analyses, we identified two further regions of interest on chromosomes 4q and 15q. Using linked pedigrees, we localized 3centr and 18q to 9.8 and 12.2 cM, respectively, with potential for further localization with the addition of markers in specific pedigrees. Our success in replication and novel locus identification illustrates the utility of large extended pedigrees for common disorders, such as MDD. Further, it supports the hypothesis that MDD and anxiety disorders have over-lapping genetic etiologies and suggests that comorbid diagnoses may be useful in defining more genetically homogeneous forms of MDD for linkage mapping.
Subject(s)
Anxiety Disorders/genetics , Depressive Disorder/genetics , Genetic Linkage/genetics , Genetic Predisposition to Disease/genetics , Genome, Human , Anxiety Disorders/psychology , Chromosomes, Human, Pair 18/genetics , Chromosomes, Human, Pair 3/genetics , Chromosomes, Human, Pair 7/genetics , Depressive Disorder/psychology , Family Health , Female , Genotype , Humans , Lod Score , Male , Microsatellite Repeats , Pedigree , Recurrence , Sex Factors , UtahABSTRACT
Major depression disorder is a common psychiatric disease with a major economic impact on society. In many cases, no effective treatment is available. The etiology of major depression is complex, but it is clear that the disease is, to a large extent, determined genetically, especially among individuals with a familial history of major depression, presumably through the involvement of multiple predisposition genes in addition to an environmental component. As a first step toward identification of chromosomal loci contributing to genetic predisposition to major depression, we have conducted a genomewide scan by using 628 microsatellite markers on 1,890 individuals from 110 Utah pedigrees with a strong family history of major depression. We identified significant linkage to major depression in males at marker D12S1300 (multipoint heterogeneity LOD score 4.6; P=.00003 after adjustment for multiple testing). With additional markers, the linkage evidence became highly significant, with the multipoint heterogeneity LOD score at marker D12S1706 increasing to 6.1 (P=.0000007 after adjustment for multiple testing). This study confirms the presence of one or more genes involved in psychiatric diseases on the q arm of chromosome 12 and provides strong evidence for the existence of a sex-specific predisposition gene to major depression at 12q22-q23.2.
