Associations Among PTSD, Cognitive Functioning, and Health-Promoting Behavior in Post-9/11 Veterans.

INTRODUCTION: PTSD is associated with negative health behaviors that increase chronic disease risk, yet health behaviors and their determinants are not well investigated in this context. One understudied mechanism of health behaviors is cognitive functioning. Deficits in cognitive functioning may undermine engagement in health-promoting behavior, thereby increasing the negative impact of PTSD. We tested three hypotheses: (1) Greater PTSD symptom severity is associated with less health-promoting behavior; (2) greater PTSD symptom severity is associated with poorer cognitive functioning across verbal memory, processing speed, attention, and executive functioning domains; and (3) verbal memory and executive functioning exhibit indirect effects on the relationship between PTSD and health-promoting behavior. MATERIALS AND METHODS: We examined associations between PTSD symptom severity (Clinician-Administered PTSD Scale for DSM-IV), cognitive functioning, and health-promoting behavior (Health-Promoting Lifestyle Profile II) in 124 post-9/11 veterans (average age = 37.82; 85.5% male; 63.7% White; 18.5% Black; 26.6% Hispanic). Cognitive domains examined included verbal memory (California Verbal Learning Test), processing speed (Digit Symbol Coding), attention and working memory (Digit Span), and executive functions (Trail Making Test and Stroop Interference). RESULTS: Regression analyses indicated that greater PTSD symptom severity was associated with less health-promoting behavior (B = -.0101, SE = 0.0016, P < .0001; R2 = 0.3052). Path analyses revealed that verbal learning and memory partially accounted for this relationship (R2 = 0.037- 0.043; P < .05). CONCLUSIONS: Therapeutic targeting of these relationships may have implications for the prevention of long-term disease impact in veterans; longitudinal research is needed to elucidate the potential impact on chronic disease.

Interactive association of posttraumatic stress disorder, apolipoprotein ε4 genotype, and age on cognitive functioning.

BACKGROUND: The ε4 allele of the apolipoprotein (APOE) gene and posttraumatic stress disorder (PTSD) are associated with cognitive deficits. Both associations may vary depending on age. No previous study has examined a possible three-way interaction between APOE ε4, PTSD, and age on cognitive functioning. METHODS: Data were analyzed from 1244 European-American U.S. military veterans who participated in the 2011 National Health and Resilience in Veterans Study (NHRVS). Analyses of covariance were used to examine the main effects and interactions of APOE ε4, PTSD, and age on learning/working memory (LWM) and attention/psychomotor (APM) performance. RESULTS: A significant three-way interaction between APOE ε4, PTSD, and age on the LWM composite (ηp 2  = 0.011) was observed such that the main effect of APOE ε4 on LWM was only significant for older participants with PTSD. A significant two-way interaction between PTSD and age on the APM composite (ηp 2  = 0.011) was observed such that the main effect of PTSD on APM was only significant in older participants. CONCLUSION: Older APOE ε4 carriers with probable PTSD showed poorer LWM performance relative to other groups. Aging-related associations on APM performance were most pronounced in veterans with PTSD. These data are preliminary evidence that identification and treatment of PTSD may be beneficial for individuals at risk for age-related cognitive impairment.

A Pilot Study of a Three-Session Heart Rate Variability Biofeedback Intervention for Veterans with Posttraumatic Stress Disorder.

Many veterans do not complete traditional trauma treatments; others may continue to struggle with posttraumatic stress disorder (PTSD) even after completing a full course of therapy (Blasé et al., in Int J Environ Res Public Health 18(7):Article 3329, https://doi.org/10.3390/ijerph18073329 , 2016). Heart rate variability (HRV) biofeedback (HRVB) is a non-invasive, non-pharmacological, breathing-based cardiorespiratory training technique that can reduce trauma symptoms and improve HRV parameters. Prior studies have demonstrated HRVB is well-tolerated by veterans with PTSD symptoms (Tan et al., in Appl Psychophysiol Biofeedback 36(1):27-35, 10.1007/s10484-010-9141-y, 2011; Schuman and Killian, in Appl Psychophysiol Biofeedback 44(1):9-20, https://doi.org/10.1007/s10484-018-9415-3 , 2019). This randomized wait-list controlled pilot study tested a short mobile app-adapted HRVB intervention in combination with treatment as usual for veterans with military-related PTSD to determine if further investigation was warranted. We assessed veterans' military-related PTSD symptoms, depression symptoms, and HRV time and frequency domain measures at baseline, after three clinical sessions, and one month later. This study combined clinical training and home biofeedback with a smartphone app and sensor to reinforce training and validate adherence. In the intervention group, depression and SDNN significantly improved, and we observed marginally significant improvements for PTSD Cluster B (intrusion) symptoms, whereas no significant improvements were observed in the control group. In addition, the brief protocol was acceptable to veterans with PTSD with over 83% of participants completing the study. However, adherence to home practice was low. Findings suggest brief HRVB interventions can decrease comorbid depression and improve overall autonomic function in veterans with PTSD; however, additional research on home biofeedback is necessary to determine the best strategies to increase adherence and which veterans would benefit from brief HRVB interventions.

Temporal Sequencing of Mental Health Symptom Severity and Suicidal Ideation in Post-9/11 Men and Women Veterans Who Recently Separated from the Military.

BACKGROUND: Despite some evidence for gender differences in associations between military veterans' mental health and suicidal ideation (SI), gender-specific prospective studies are lacking. The aims of this prospective study were to: (1) examine gender differences in veterans' initial status and trajectories of mental health severity and SI status and (2) identify temporal sequencing of mental health predictors of SI. METHODS: Surveys of 1035 US veterans were administered at 3 time-points (T1, T2, T3) over a 7-year period following military separation, with an initial assessment within 2 years of military separation. RESULTS: Men reported higher baseline PTSD and alcohol misuse severity than women. No baseline gender difference in SI prevalence was detected. Baseline gender differences in mental health severity were maintained over time. For both men and women, remittance of SI was more likely from T1 to T2 than from T2 to T3 while chronic SI was more likely from T2 to T3. The strongest predictors of T3 SI were prior SI followed by alcohol misuse, depression, and PTSD severity with stronger effects for T2 predictors than T1. CONCLUSION: The maintenance of baseline gender differences throughout trajectories of mental health predictors of SI supports the need for ongoing gender-specific mental health services. Current governmental interorganizational efforts are focused on suicide prevention during the first year after military service completion. Our findings indicate a need to extend mental health screening and treatment beyond the early post-military period to reduce risk and recurrence of SI for both men and women.

Mental Health and Psychosocial Functioning in Recently Separated U.S. Women Veterans: Trajectories and Bi-Directional Relationships.

Prior research on the relationship between veterans' mental health and psychosocial functioning has primarily relied on male samples. Here, we investigated prospective longitudinal relationships between mental health and psychosocial functioning in 554 female Iraq and Afghanistan War veterans who were surveyed three times between two- and seven-years following separation from service. Mixed effects modeling revealed that increasing depression and posttraumatic stress disorder (PTSD) severity predicted declines in work functioning. Increasing PTSD severity predicted declining parental functioning and worsening depression predicted a decline in relationship functioning. In turn, decreased work and intimate relationship functioning predicted increased PTSD and depression symptom severity suggesting bi-directional effects between mental health and psychosocial functioning. An examination of the effect of deployment stressors on psychosocial functioning revealed that deployment sexual harassment was the strongest predictor of decreased psychosocial functioning across all domains. Evidence for the reciprocal nature of relationships between mental health and psychosocial functioning underscore the need for treatment targeted at PTSD and depression, as well as work and relationship functioning to improve outcomes for women veterans.

Risk and protective factors of dementia among adults with post-traumatic stress disorder: a systematic review protocol.

INTRODUCTION: Post-traumatic stress disorder (PTSD) is associated with an increased risk of dementia. Individual epidemiological studies have controlled for several confounders of the relationship between PTSD and increased dementia risk, yet particular risk factors underlying this relationship have not been determined. This systematic review protocol aims to identify risk and protective factors of dementia among adults with PTSD. METHODS AND ANALYSIS: We will conduct an electronic search of the databases: PubMed, CINAHL, PsychINFO, The Cochrane Library, Scopus and ProQuest Dissertation and Theses Global. After screening the studies, quantitative synthesis will be performed, if possible. Otherwise, a narrative synthesis will be performed. We will include randomised controlled trials and other types of research evidence including longitudinal cohort studies. Strength of evidence will be assessed using the Grading of Recommendations, Assessment, Development and Evaluations method. Examples of variables that will be extracted are: year of PTSD diagnosis, comorbid conditions, health behaviours, pharmacological treatments and year of mild cognitive impairment or dementia diagnosis. We developed this systematic review protocol according to the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols 2015 statement. ETHICS AND DISSEMINATION: The proposed study will not collect individual-level data and, therefore, does not require ethical approval. Results of this study will provide current evidence on risk and protective factors of dementia in adults with PTSD. Findings will be disseminated in peer-reviewed publications and conference presentations. PROSPERO REGISTRATION NUMBER: CRD42019128553.

Cis-regulatory basis of sister cell type divergence in the vertebrate retina.

Multicellular organisms evolved via repeated functional divergence of transcriptionally related sister cell types, but the mechanisms underlying sister cell type divergence are not well understood. Here, we study a canonical pair of sister cell types, retinal photoreceptors and bipolar cells, to identify the key cis-regulatory features that distinguish them. By comparing open chromatin maps and transcriptomic profiles, we found that while photoreceptor and bipolar cells have divergent transcriptomes, they share remarkably similar cis-regulatory grammars, marked by enrichment of K50 homeodomain binding sites. However, cell class-specific enhancers are distinguished by enrichment of E-box motifs in bipolar cells, and Q50 homeodomain motifs in photoreceptors. We show that converting K50 motifs to Q50 motifs represses reporter expression in bipolar cells, while photoreceptor expression is maintained. These findings suggest that partitioning of Q50 motifs within cell type-specific cis-regulatory elements was a critical step in the evolutionary divergence of the bipolar transcriptome from that of photoreceptors.

Civic Service as an Intervention to Promote Psychosocial Health and Implications for Mental Health in Post-9/11/01 Era Women Veterans.

Background: Women veterans experience significant morbidity with poorer health and mental health outcomes relative to nonveteran counterparts. Little is known about how to best promote health and well-being among reintegrating female veterans. Civic service has been shown to improve mental health in civilians, but its impact on female veterans is unknown. This study characterizes the physical and mental health and psychosocial functioning of female veterans and evaluates changes in these domains following completion of an intensive civic service program. Materials and Methods: Data were obtained from an observational, pre-post cohort study of post-9/11/01 era veterans who completed a 6-month, 20-hour per week civic service program. Of the 346 participants, 107 were women. Participants completed online pre- and post-program surveys. Nine measures of health, mental health, and psychosocial functioning were analyzed. Results: Before starting the program, 47% of women screened positive for a probable diagnosis of post-traumatic stress disorder (PTSD), 24% for depression, and 51% reported seeking assistance for mental health problems. Pre-post change scores indicated significant improvements on nine measures of health, mental health, and psychosocial functioning (p < 0.05). Perceived self-efficacy change scores predicted PTSD change scores, F(1, 93) = 8.00, p < 0.05. Seeking professional assistance for mental health problems and social isolation and loneliness change scores predicted depression change scores, F(2, 95) = 15.618, p < 0.05, explaining 23% of the variance. Conclusions: Civic service has the potential to promote and support the maintenance of psychosocial well-being for returning post-9/11/01 era women veterans with symptoms of PTSD or depression.

An initial review of residual symptoms after empirically supported trauma-focused cognitive behavioral psychological treatment.

OBJECTIVE: Although residual symptoms remain following clinical treatment for posttraumatic stress disorder (PTSD), little is known about the characteristics of these residual symptoms. We aimed to determine the type, severity, and frequency of symptoms that remain after trauma-focused psychotherapy. METHODS: We conducted a systematic review of 51 randomized controlled trials of empirically supported psychosocial interventions for PTSD (68 total treatment arms). Outcomes included: 1) PTSD symptoms and 2) conditions commonly comorbid with PTSD: depression, anxiety, and quality of life impairment. RESULTS: In general, the results revealed that participants who completed PTSD treatment continued to report residual PTSD symptoms: 31% reported clinical symptom levels, and 59% reported subthreshold levels at posttreatment, particularly within the hyperarousal cluster. Residual symptoms also emerged for depression (19% clinical), anxiety (55% clinical), and quality of life (36% clinical). Few differences emerged across treatment types, but differential patterns were revealed for sample/trauma types. CONCLUSIONS: Results suggest a need for focused research attention to and clinical assessment of individual residual symptoms following empirically supported treatment for PTSD to determine whether further treatment sessions are warranted.

Lifespan Socioeconomic Context: Associations With Cognitive Functioning in Later Life.

Objectives: Early socioeconomic status (SES) correlates with later-life cognition. However, the effect of socioeconomic context (SEC), which reflects influences from broader ecological contexts, has not been examined. The present study developed a measure of SEC using lifetime residential addresses and examined SEC and residential mobility effects on later-life cognition. Method: Older adults (N = 117, Mage = 75) reported addresses since birth. Latent SEC was constructed from census income, employment, and education (1920-2010) for each county and census year, extrapolated between census years. Controlling for current SES, SEC in childhood (ages 0-18) and adulthood (ages 19-60), with finer granulations in young adulthood (ages 19-39) and midlife (ages 40-60), predicted later-life cognition. Effects of residential mobility on later-life cognition were also examined. Results: Higher childhood and adulthood SEC were associated with better Auditory Verbal Learning Test recognition (ß = .24, p = .012) and immediate recall (ß = .26, p = .008). Higher midlife SEC was associated with faster task switching (ß = .26, p = .025) and better task switching efficiency (ß = .27, p = .022). Higher residential mobility in childhood was associated with higher crystallized intelligence (ß = .194, p = .040). Discussion: Independent of current SES, childhood and adulthood SEC predicted later-life cognition, which may be sensitive to effects of social institutions and environmental health. SEC assessed across the lifespan, and related residential mobility information may be important complements to SES in predicting later-life cognitive health.

Broadcasting War Trauma: An Exploratory Netnography of Veterans' YouTube Vlogs.

This exploratory netnographic study is among the first to investigate military video blogs (milvlogs) posted by Iraq and Afghanistan veterans who self-published stories on military-related trauma to YouTube. Studies have shown that self-published milvlogs provide benefits such as education, social support, and self-management of chronic physical and psychological illness. The aim of this study was to explore combat veterans' milvlogs and to determine themes that emerged across the videos. We transcribed and analyzed content from 17 milvlogs. Our analysis yielded seven themes: motivation, loss, managing symptoms, help-seeking, guilt and shame, suicide, and connecting to other veterans. We concluded that veterans were initially drawn to vlogging to connect to others. Vlogging also served as a medium for combat veterans to tell their stories, position these stories against others' experiences, and engage in outreach and advocacy. Finally, milvlogs may provide an easily accessible resource for developing preventive and/or mental health treatment/support links.

Metachronous gastric metastasis from lung primary, with synchronous pancreatic neuroendocrine carcinoma.

The finding of gastric metachronous metastasis, several years after the diagnosis of primary lung large cell carcinoma is rare and incidental. Even more extremely rare is the finding of a synchronous primary pancreas cancer. EUS-FNA with immunohistochemistry is useful for diagnosing metastatic lesions and differentiating those from synchronous primary lesions.

Utilization of direct smears of thyroid fine-needle aspirates for ancillary molecular testing: A comparison of two proprietary testing platforms.

BACKGROUND: Ancillary molecular testing has been recommended for thyroid fine-needle aspirates (FNA) with indeterminate cytologic diagnoses. Rosetta Genomics and Interpace Diagnostics have developed assays that can utilize direct smears as the testing substrate. METHODS: A retrospective study of indeterminate thyroid FNAs with known histologic follow-up was performed. One Diff-Quik-stained smear and one Papanicolaou-stained smear with similar cellularity (at least 60-100 lesional cells) from each case were sent to Rosetta and Interpace, respectively, for analysis. The results were directly compared and correlated with the final histopathology. Neither company was aware of the follow-up histologic findings in these cases. RESULTS: A total of 10 thyroid FNAs were identified from our 2015 files. The cytologic diagnoses included follicular lesion of undetermined significance (FLUS, n = 5), follicular neoplasm/suspicious for follicular neoplasm (FN/SFN, n = 4), and suspicious for malignancy (SM, n = 1). Of the seven cases with benign histology, six smears were classified as benign by the RosettaGX microRNA classifier, and one case was designated as suspicious. Five cases were negative by both ThyGenX oncogene panel and ThyraMIR microRNA classifier. One case was negative by ThyGenX and positive on follow-up ThyraMIR, and one case was positive for KRAS mutation and positive on ThyraMIR. Both the RosettaGX and ThyGenX/ThyraMIR tests demonstrated positive results for the three histologically malignant cases. CONCLUSION: This study demonstrates that two molecular testing platforms performed equally well using our stained direct smears. Both molecular tests revealed a 100% negative predictive rate. RosettaGX showed a 75% positive predictive value in comparison to 60% for ThyGenX/ThyraMIR.

Perceived family impact of volunteering among reintegrating Post-9/11 veterans.

Family issues are common among returned Post-9/11 veterans. Traumatic brain injury (TBI), posttraumatic stress disorder (PTSD), and depression are each independently related to divorce while community ties and social support are protective factors for the family during reintegration. Evidence from elders on the benefits of one intervention, community volunteering, may indicate "spillover effects" of these benefits into the family. Few measures exist to assess the impact of military veteran volunteering on the family. We report: (1) an adaption of a benefits measure from elders to veterans, (2) its preliminary reliability and validity, and (3) differences among subgroups. Reintegrating Post-9/11 veterans (N = 346) who completed a 6-month, stipended volunteer program were surveyed. Perceived impact of volunteering on the family was assessed after completion of the program using an 11-item self-report measure. Rank-based nonparametric tests were used to detect significant differences among subgroups. Preliminary findings support the scale's adaptation to veterans, internal consistency, and construct validity. At least one perceived family impact indicator differed significantly (p < .05) between subgroups based on demographic and psychological factors. Veterans in this civic service program perceived that their volunteering may have impacted their families.

Completion of a Veteran-Focused Civic Service Program Improves Health and Psychosocial Outcomes in Iraq and Afghanistan Veterans With a History of Traumatic Brain Injury.

INTRODUCTION: Volunteering as a health promotion intervention is positively related to improved health and well-being in civilians and older adults. Yet, the impacts of participating in a community-based volunteering program on returning military veterans have not been studied, nor have the outcomes for veterans who have experienced a traumatic brain injury (TBI). MATERIALS AND METHODS: This observational, pre-post survey examines health, psychological, and social outcomes from a cohort of post-9/11/01 veterans with (N = 67) and without a reported TBI history (N = 273) who completed a 6-month, 20-hour per week veteran-focused civic service program. This study was approved by the Saint Louis University Institutional Review Board. RESULTS: Veterans with a TBI history who completed the 6-month civic service program conducted by a veteran-focused national nonprofit organization showed significant pre-post improvement (p < 0.05) in overall health, decreased post-traumatic stress disorder (PTSD) symptoms, increased perceived self-efficacy, decreased feelings of isolation and loneliness, and increased perceived availability of social support. These significant findings were not due to participants seeking external help for emotional problems. Out of four aspects of PTSD symptomatology assessed, "feeling numb or detached from others, activities, or surroundings" most accounted for the decrease in PTSD scores. Given this and taken together with the significant decrease in social isolation and loneliness and the social nature of the program, we posit that decreased social isolation and loneliness is the primary driver of the improved psychological and social outcomes documented here. Finally, pre-post change scores did not differ significantly between veterans with and without a TBI, indicating that TBI history did not hinder the ability to benefit from this program. CONCLUSION: Completion of this civic service program positively impacted veterans with TBI, especially on psychological and social outcomes important to recovery and life satisfaction after TBI. Civic service may provide an innovative approach to promoting wellness in returning veterans with a TBI. Results of this study provide preliminary evidence that civic service decreases social isolation and loneliness in veterans with a reported TBI history. Given our findings, volunteering may prevent against social isolation and be promotional of perceived social support in veterans with TBI.

The impact of a civic service program on biopsychosocial outcomes of post 9/11 U.S. military veterans.

Volunteering as a health promotion intervention, improves physical health, mental health, and social outcomes particularly in older adults, yet limited research exists for veterans. We conducted a preliminary study to explore whether volunteering impacts a variety of biopsychosocial outcomes, including symptoms of post-traumatic stress disorder (PTSD) and depression, among returning military veterans from Iraq and Afghanistan. A survey enrolling a prospective cohort of United States (U.S.) veterans who served in the military after 11 September 2001 and who participated in a national civic service program was conducted. A total of 346 veterans completed standardized health, mental health, and psychosocial self-report measures before and after the program. Statistically significant differences were detected in overall health rating, level of emotional difficulty, PTSD and depression symptoms, purpose in life, self-efficacy, social isolation, and the perceived availability of social support at program completion. Screening positive for probable PTSD predicted improved perceived self-efficacy while probable depression predicted a decrease in loneliness, an increase in purpose in life, and an increase in perceived social support, at program completion. Volunteering was associated with significant improvements in health, mental health and social outcomes in returning veterans.

Transcriptome profiling of developing photoreceptor subtypes reveals candidate genes involved in avian photoreceptor diversification.

Avian photoreceptors are a diverse class of neurons, comprised of four single cones, the two members of the double cone, and rods. The signaling events and transcriptional regulators driving the differentiation of these diverse photoreceptors are largely unknown. In addition, many distinctive features of photoreceptor subtypes, including spectral tuning, oil droplet size and pigmentation, synaptic targets, and spatial patterning, have been well characterized, but the molecular mechanisms underlying these attributes have not been explored. To identify genes specifically expressed in distinct chicken (Gallus gallus) photoreceptor subtypes, we developed fluorescent reporters that label photoreceptor subpopulations, isolated these subpopulations by using fluorescence-activated cell sorting, and subjected them to next-generation sequencing. By comparing the expression profiles of photoreceptors labeled with rhodopsin, red opsin, green opsin, and violet opsin reporters, we have identified hundreds of differentially expressed genes that may underlie the distinctive features of these photoreceptor subtypes. These genes are involved in a variety of processes, including phototransduction, transcriptional regulation, cell adhesion, maintenance of intra- and extracellular structure, and metabolism. Of particular note are a variety of differentially expressed transcription factors, which may drive and maintain photoreceptor diversity, and cell adhesion molecules, which may mediate spatial patterning of photoreceptors and act to establish retinal circuitry. These analyses provide a framework for future studies that will dissect the role of these various factors in the differentiation of avian photoreceptor subtypes.

Transcriptional regulation of neural retina leucine zipper (Nrl), a photoreceptor cell fate determinant.

The transcription factor neural retina leucine zipper (Nrl) is a critical determinant of rod photoreceptor cell fate and a key regulator of rod differentiation. Nrl(-/-) rod precursors fail to turn on rod genes and instead differentiate as cones. Furthermore, NRL mutations in humans cause retinitis pigmentosa. Despite the developmental and clinical significance of this gene, little is known about the transcriptional regulation of Nrl itself. In this study, we sought to define the cis- and trans-acting factors responsible for initiation and maintenance of Nrl transcription in the mouse retina. Utilizing a quantitative mouse retinal explant electroporation assay, we discovered a phylogenetically conserved, 30-base pair region immediately upstream of the transcription start site that is required for Nrl promoter activity. This region contains binding sites for the retinal transcription factors CRX, OTX2, and RORß, and point mutations in these sites completely abolish promoter activity in living retinas. Gel-shift experiments show that CRX, OTX2, and RORß can bind to the critical region in vitro, whereas ChIP experiments demonstrate binding of CRX and OTX2 to the critical region in vivo. Thus, our results indicate that CRX, OTX2, and RORß directly regulate Nrl transcription by binding to critical sites within the Nrl promoter. We propose a model in which Nrl expression is primarily initiated by OTX2 and RORß and later maintained at high levels by CRX and RORß.

CRX ChIP-seq reveals the cis-regulatory architecture of mouse photoreceptors.

Approximately 98% of mammalian DNA is noncoding, yet we understand relatively little about the function of this enigmatic portion of the genome. The cis-regulatory elements that control gene expression reside in noncoding regions and can be identified by mapping the binding sites of tissue-specific transcription factors. Cone-rod homeobox (CRX) is a key transcription factor in photoreceptor differentiation and survival, but its in vivo targets are largely unknown. Here, we used chromatin immunoprecipitation with massively parallel sequencing (ChIP-seq) on CRX to identify thousands of cis-regulatory regions around photoreceptor genes in adult mouse retina. CRX directly regulates downstream photoreceptor transcription factors and their target genes via a network of spatially distributed regulatory elements around each locus. CRX-bound regions act in a synergistic fashion to activate transcription and contain multiple CRX binding sites which interact in a spacing- and orientation-dependent manner to fine-tune transcript levels. CRX ChIP-seq was also performed on Nrl(-/-) retinas, which represent an enriched source of cone photoreceptors. Comparison with the wild-type ChIP-seq data set identified numerous rod- and cone-specific CRX-bound regions as well as many shared elements. Thus, CRX combinatorially orchestrates the transcriptional networks of both rods and cones by coordinating the expression of photoreceptor genes including most retinal disease genes. In addition, this study pinpoints thousands of noncoding regions of relevance to both Mendelian and complex retinal disease.