Association of functional polymorphisms from brain-derived neurotrophic factor and serotonin-related genes with depressive symptoms after a medical stressor in older adults

Depressive symptoms are common in older adults after a disabling medical event and interfere with rehabilitation and recovery from the disability. This prospective study examined the role of genetic polymorphisms implicated in synaptic integrity and stress-associated depression as predictors of depressive symptoms after hip fracture. We recruited healthy comparisons from the community and participants with hip fracture after surgical fixation from Saint Louis, Missouri hospitals. We examined the valine (Val) to methionine (Met) polymorphism in brain-derived neurotrophic factor (BDNF), serotonin 1A receptor (5HT1a-rs6295) polymorphism, and the serotonin transporter-linked polymorphic region (5HTTLPR) interaction with the rs25531 A to G single nucleotide polymorphism (5HTTLPR-rs25531) as predictors of depressive symptoms. We also examined whether depressive symptoms mediate the influence of BDNF genotype on functional recovery. Among 429 participants with hip fracture, BDNF Met/Met carriers developed significantly more depressive symptoms than Val/Val carriers during a four-week period after the fracture (p=.012). BDNF genotype also predicted functional recovery over the ensuing year, mediated by its effects on depressive symptoms (CI: 0.07-3.37). Unlike prior studies of stressful life events, the S' 5HTTLPR-rs25531 variant did not predict higher levels of depressive symptoms; instead, we report an exploratory finding of an epistatic effect between BDNF and 5HTTLPR-rs25531 whereby the compounded effects of two LA alleles and BDNF Met/Met genotype elevate risk of depressive symptoms after hip fracture (p=.006). No differences between 5HT1a genotypes were found. Our findings suggest plasticity-related genetic factors contribute to the neural mechanisms of mental and functional well-being after a disabling medical stressor

Mediation model using Hayes’ (2013) multicategorical independent variable method

<p>. Mediation test of the relationship between brain-derived neurotrophic factor (<i>BDNF</i>) Val66Met polymorphism and the Functional Recovery Score (FRS) at week 12 as a result of the Montgomery-Asberg Depression Rating Scale (MADRS) depression scores. Results are shown for the <i>BDNF</i> Val+:Met/Met contrast. The Val/Val:Val/Met contrast was not significant.</p

Observed Montgomery-Asberg Depression Rating Scale (MADRS) scores over time for participants with hip fracture and healthy comparisons.

<p>The number of participants with hip fracture and healthy comparisons are listed below the figure.</p

Observed Montgomery-Asberg Depression Rating Scale (MADRS) scores for participants with hip fracture.

<p>Observed Montgomery-Asberg Depression Rating Scale (MADRS) scores for participants with hip fracture.</p

Predicted values for the interaction effect between brain-derived neurotrophic factor (<i>BDNF</i>) and serotonin transporter gene-linked polymorphic region, 5HTTLPR-rs25531

<p>. Within hip fracture participants with two 5HTTLPR-rs25531 LA alleles (LA/LA), contrast results for the GEE analysis indicate <i>BDNF</i> Met/Met carriers had significantly higher depressive symptoms than Val/Val carriers (χ² = 4.37(1), p = .037) and Val/Met carriers (χ² = 3.86(1), p = .05). Sample sizes are listed below each graph. Abbreviations: MADRS, Montgomery-Asberg Depression Rating Scale; GEE, Generalized estimating equations.</p

Baseline demographic variables and summary of frequencies for <b><i>BDNF</i></b> Val66Met, 5HTTLPR-rs25531, and C(-1019)G 5HT1a (Caucasian only).

<p>Abbreviations: 5HT1a, Serotonin 1A receptor; 5HTTLPR, serotonin transporter gene-linked polymorphic region; <i>BDNF</i>, brain-derived neurotrophic factor; MADRS, Montgomery-Asberg Depression Rating Scale.</p><p>^aReduced N</p><p>Baseline demographic variables and summary of frequencies for <b><i>BDNF</i></b> Val66Met, 5HTTLPR-rs25531, and C(-1019)G 5HT1a (Caucasian only).</p

Parameter estimates (log) and empirical standard error estimates with time for four GEE models predicting MADRS depressive scores post-fracture.

<p>Abbreviations: 5HT1a, Serotonin 1A receptor; 5HTTLPR, serotonin transporter gene-linked polymorphic region; <i>BDNF</i>, brain-derived neurotrophic factor; BL, baseline; GEE, generalized estimating equation; MADRS, Montgomery-Asberg Depression Rating Scale.</p><p>The estimated intercept (log) for each of the models refers to MADRS depressive scores for carriers of the reference (common homozygote) genotype. For example, irrespective of <i>BDNF</i> genotype, the intercept for all participants with hip fracture was 1.72 and relative to Val/Val carriers, Met/Met carriers had 0.39 units higher MADRS scores. The interaction estimates are interpreted as follows:</p><p>^aThe difference between Met/Met carriers and Val/Val carriers within LA/LA minus the difference between Met/Met carriers and Val/Val carriers within S′/S′.</p><p>^bThe difference between Met/Met carriers and Val/Val carriers within LA/LA minus the difference between Met/Met carriers and Val/Val carriers within LA/S′.</p><p>^cThe difference between Val/Met carriers and Val/Val carriers within LA/LA minus the difference between Val/Met carriers and Val/Val carriers within S′/S′.</p><p>^dThe difference between Val/Met carriers and Val/Val carriers within LA/LA minus the difference between Val/Met carriers and Val/Val carriers within LA/S′.</p><p>^eContrast results for GEE analysis of the interaction indicate a significant difference between <i>BDNF</i> Met/Met and Val/Val carriers within LA/LA (<i>χ</i>² = 4.37(1), p = .037) and between <i>BDNF</i> Met/Met and Val/Met carriers within LA/LA (<i>χ</i>² = 3.86(1), p = .050).</p><p>Parameter estimates (log) and empirical standard error estimates with time for four GEE models predicting MADRS depressive scores post-fracture.</p