Genome-wide linkage analysis of a composite index of neuroticism and mood-related scales in extreme selected sibships

Abstract

There is considerable evidence to suggest that the genetic vulnerabilities to depression and anxiety substantially overlap and quantitatively act to alter risk to both disorders. Continuous scales can be used to index this shared liability and are a complementary approach to the use of clinical phenotypes in the genetic analysis of depression and anxiety. The aim of this study (Genetic and Environmental Nature of Emotional States in Siblings) was to identify genetic variants for the liability to depression and anxiety after the application of quantitative genetic methodology to a large community-based sample (n = 34,371), using four well-validated questionnaires of depression and anxiety. Genetic model fitting was performed on 2658 unselected sibships, which provided evidence for a single common familial factor that accounted for a substantial proportion of the genetic variances and covariances of the four scales. Using the parameter estimates from this model, a composite index of liability (G) was constructed. This index was then used to select a smaller--but statistically powerful--sample for DNA collection (757 individuals, 297 sibships). These individuals were genotyped with more than 400 microsatellite markers. After the data were checked and cleaned, linkage analysis was performed on G and the personality scale of neuroticism using the regression-based linkage program MERLIN-REGRESS. The results indicated two potential quantitative trait loci (QTL): one on chromosome 1p (LOD 2.2) around 64 cM (43-70 cM) near marker D1S2892 and another on chromosome 6p (LOD 2.7) around 47 cM (34-63 cM) near marker D6S1610. Further exploratory sex-specific analyses suggested that these QTLs might have sex-limited effects.

Relationship between Cortisol Responses to Stress and Personality

“…It is conceivable that this function is related to biological differences that are manifest in the personality attributes. In a genomewide linkage scan of neuroticism, a region on chromosome 6p was identified with a LOD score of 3.9 in male-male sibling pairs, while the same region had almost no signal in female-female pairs (Nash et al, 2004). If this finding were to lead to the cloning of a sex-specific neuroticism gene, it would be possible to construe that the biological basis for personality domains may be different in the sexes and that this difference may influence the relationship of stress to the HPA axis.…”

Linkage on chromosome 14 in a genome-wide linkage study of a broad anxiety phenotype

“…In MERLIN-regress, repeated measures can be entered in the analysis as an average across occasions with further specification of the test-retest correlation and the number of measurements for each individual (in this case, varying from 1 to 5) to readjust the trait variance. 38 The intra-class correlation between the five measures was estimated in SPSS using a mixed model procedure, which allows using all available data, even of the subjects who did not participate every occasion.…”

A whole genome association study of neuroticism using DNA pooling

“…[6][7][8][9] The correlation between anxiety, major depression and neuroticism is, in part, due to the presence of shared genetic factors, [10][11][12][13] an observation that has spurred attempts to map the genetic basis of neuroticism. [14][15][16] It is much easier to acquire the large samples necessary for genetic studies of neuroticism, which is assessed using a self-administered questionnaire, than it is to acquire large patient samples that require diagnostic interviews for accurate assessment of major depression and anxiety.…”

“…One study of extremely discordant and concordant siblings identified five loci that exceeded a 5% genomewide significance threshold, 14 but a second study, also using a selected sample, failed to identify any genome-wide significant signals. 15 One explanation for the difficulties encountered is that the proportion of genetic variance attributable to an individual locus is extremely small, so that the linkage studies are underpowered. A recent survey of some 50 metaanalyses and 752 individual studies concluded that the typical effect sizes of individual genetic variants for complex disease ranged from 1.2 to 1.6.…”