A common and functional mineralocorticoid receptor haplotype enhances optimism and protects against depression in females

Abstract

Mineralocorticoid (MR) and glucocorticoid receptors (GR) are abundantly expressed in the limbic brain and mediate cortisol effects on the stress-response and behavioral adaptation. Dysregulation of the stress response impairs adaptation and is a risk factor for depression, which is twice as abundant in women than in men. Because of the importance of MR for appraisal processes underlying the initial phase of the stress response we investigated whether specific MR haplotypes were associated with personality traits that predict the risk of depression. We discovered a common gene variant (haplotype 2, frequency ∼0.38) resulting in enhanced MR activity. Haplotype 2 was associated with heightened dispositional optimism in study 1 and with less hopelessness and rumination in study 2. Using data from a large genome-wide association study we then established that haplotype 2 was associated with a lower risk of depression. Interestingly, all effects were restricted to women. We propose that common functional MR haplotypes are important determinants of inter-individual variability in resilience to depression in women by differentially mediating cortisol effects on the stress system.

Figure 1

(a) Schematic overview of the human mineralocorticoid receptor (MR) gene with its respective 5′ haplotypes and haplotype frequencies. Three haplotypes along a stretch of 4 kb of the 5′ untranslated region were identified based on the genotypes of 50 anonymous DNA samples and include eight single-nucleotide polymorphisms (SNPs). The positioning and relation with the -2G/C (rs2070951) and I180 V (rs5522, control SNPs in grey) SNPs are indicated, which tag these three most common haplotypes. The haplotypes are not linked to common SNPs more 3′ in the MR gene sequence, as a recombination hotspot exists in intron 2 (asterisk). (b) Mean activity (±s.e.m., N=6) of the human MR promoter region associated with haplotype 1, 2 or 3. The figure shows representative results (of three independent experiments with two distinct sets of plasmid isolates) on the comparison of promoter activities associated with haplotype 1–3 relative to the activity of the pGL3-Basic plasmid, which activity was set to 1 (data not shown). Activities differed significantly between the three MR plasmids (F(2,15)=27.98; P<0.001). Data are firefly luminescent signals divided by the Renilla luminescent signals, hereby controlling for cell death and variability in transfection efficiency. ^*P<0.05; ^**P<0.01; ^***P<0.001. Abbreviations: P1, promoter 1; P2, promoter 2; UTR, untranslated region.

Figure 2

Results of study 1, showing crude mean scores (±s.e.m.) for dispositional optimism according to three 5′ mineralocorticoid receptor (MR) haplotypes in women. Dispositional optimism scores increased 1.7 per haplotype 2 allele (on a range of 0 to 20) only in women (explained variance=7%) and not in men (Supplementary Table 7). To determine the effect of two haplotype 2- or 3-alleles, the effect calculated for one allele can be multiplied by 2. P-values represent adjusted comparison of haplotype 2 to the reference (haplotype 1 carriers) with linear regression. Note the breaks in the y axis.

Figure 3

(a, b) Results of study 2, showing crude mean scores (±s.e.m.) for cognitive reactivity according to three 5′ MR haplotypes in women. Hopelessness (a) scores decreased 1.1-fold per haplotype 2 allele (on a range of 0 to 20), only in women (explained variance=4%) but not in men (Supplementary Table 7). In addition, rumination (b) scores were lower only in the female haplotype 2 carriers, with a 2.1-fold reduction per haplotype 2 allele (on a range of 0 to 24; explained variance=11%). To determine the effect of two haplotype 2- or 3-alleles, the effect calculated for one allele can be multiplied by 2. P-values represent adjusted comparison of haplotype 2 to the reference (haplotype 1 carriers) with linear regression. Note the breaks in the y axis. ^* Statistical test based on transformed data. (c) Percentage of female students reporting a diagnosis for depression according to the number of haplotypes 2 (odds ratio=0.40; 95% confidence interval=0.16–0.95; P=0.04). For statistical test results see also Supplementary Table 8a.

Figure 4

Results of study 3, showing the percentage of women diagnosed with major depressive disorder (MDD) according to the number of haplotypes 2. Results are presented for the total group of women (a) (odds ratio=0.85; 95% confidence interval=0.72–1.02; P=0.08), for the women aged ⩽51 years (odds ratio=0.75; 95% confidence interval=0.60–0.93; P=0.009) (b), or for the women aged ⩽41 years (odds ratio=0.66; 95% confidence interval=0.52–0.86; P=0.002) (c). MDD cases were mainly from the Netherlands Study of Depression and Anxiety cohort (NESDA), healthy controls were mainly from the Netherlands Twin Registry (NTR). For statistical test results see Supplementary Table 8b.