Depressive symptoms are common in older adults after a disabling medical event and interfere with rehabilitation and recovery from the disability. hip fracture Met/Met carriers developed significantly more depressive symptoms than Val/Val carriers during a four-week period after the fracture (p=.012). genotype also predicted functional recovery over the ensuing 12 TIC10 months 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 obtaining of an epistatic effect between and 5HTTLPR-rs25531 whereby the compounded effects of two LA alleles and Met/Met genotype elevate TIC10 risk of depressive symptoms after hip fracture (p=.006). No differences between 5HT1a genotypes were TIC10 found. Our findings suggest plasticity-related genetic factors contribute to the neural mechanisms of mental and functional well-being after a disabling medical stressor. Introduction Disabling medical events such as hip fracture often trigger depressive symptoms. In fact most of the total burden of depressive symptoms in our TIC10 aging population occurs in the context of disabling medical events [1-3]. Hip fracture is usually a common [4] and severe life stressor [5 6 it causes pain [7] fear [8] requires hospitalization and surgery [4 6 lengthy and intensive rehabilitation [9] and leads to increased risk of institutionalization and mortality [10-12]. Depressive symptoms after hip fracture have a pernicious effect on the recovery process: they are associated with higher discharge rates to and Nefl increased length of stay in nursing homes [13-15] poorer occupational and physical therapy participation and poorer functional recovery [16 17 Hip fracture patients with more depressive symptoms are less likely to return to pre-fracture levels in several areas of physical functioning (such as walking independently) as compared to patients with less depressive symptoms [16 18 19 Currently the ability to predict which persons are at-risk of depressive symptoms after a medical disability is surprisingly low. Identification of genetic risk factors has the potential to alert caregivers to monitor patients vulnerable for high depressive symptoms. Early-intervention and optimal management of depressive symptoms could then essentially mitigate their impact on functional recovery thereby improving quality of life and functional independence in late-life. The extent to which molecular processes contribute to the neurobiology of depressive symptoms and subsequent functional recovery after a medical stressor is not well understood. Past research indicates genes associated with synaptic integrity or those vulnerable to nerve-racking events may influence depressive symptoms [20-22]. In this study we investigate genetic variants previously associated with depressive symptoms by examining their impact on both depressive symptoms and functional recovery in older adults who have experienced a medical stressor. Val66Met polymorphism Brain-derived neurotrophic factor (gene influences risk of depressive disorder in older adults [26-29]. In vivo experiments demonstrate the Met allele results in a reduction of activity-dependent BDNF secretion and a loss of BDNF protein at the synapse due to abnormal trafficking patterns [30 31 In addition the Met substitution is usually associated with reduced hippocampal activity [32] and atrophy of the hippocampus in humans [22 33 34 a structure important for mood regulation. The reduction in hippocampal volume likely reflects a decrease in BDNF protein at the synapse and consequently a decrease in synapse formation [30 35 36 Serotonin-related polymorphisms In this study we also assessed putative functional polymorphisms in serotonin (5HT) a hallmark neurotransmitter involved in depressive disorder. The gene encodes for the serotonin transporter (5HTT) and this transporter’s efficiency is usually altered by both a genetic variation of the serotonin transporter gene-linked polymorphic region (5HTTLPR) and a functional A to G single-nucleotide polymorphism (SNP; refSNP: rs25531) [37 38 5 is a 44-bp repeat insertion (long) or deletion (short) in the promoter region resulting in different levels of serotonin transporter expression.