Prevention of Alzheimer's Disease and Cognitive Decline with Diet and Lifestyle: Proceedings of the A. G. Leventis Foundation Conference.

The A. G. Leventis Foundation International Conference, "Prevention of Alzheimer's Disease and Cognitive Decline with Diet and Lifestyle", was held on May 11-12th, 2022 in Nicosia, Cyprus. This conference examined the role of diet and lifestyle for the prevention and treatment of Alzheimer's Disease and other forms of cognitive decline. Speakers from leading academic institutions presented evidence on healthy dietary patterns, with a particular focus on the traditional Mediterranean diet (MedDiet), in association with cognitive outcomes, mainly cognitive decline, dementia, and Alzheimer's disease, from both observational and interventional studies. Moreover, future directions for the potential use of olive oil, rich in polyphenols, for its therapeutic use as a nutraceutical, as well as nutritional interventions with high-quality dietary patterns (i.e. MedDiet) that support existing primarily observational evidence for the prevention of cognitive decline, as well as challenges in designing rigorous clinical trials are summarized and discussed within the conference proceedings.

Clinical and molecular practice of European thoracic pathology laboratories during the COVID-19 pandemic. The past and the near future.

BACKGROUND: This study evaluated the consequences in Europe of the COVID-19 outbreak on pathology laboratories orientated toward the diagnosis of thoracic diseases. MATERIALS AND METHODS: A survey was sent to 71 pathology laboratories from 21 European countries. The questionnaire requested information concerning the organization of biosafety, the clinical and molecular pathology, the biobanking, the workload, the associated research into COVID-19, and the organization of education and training during the COVID-19 crisis, from 15 March to 31 May 2020, compared with the same period in 2019. RESULTS: Questionnaires were returned from 53/71 (75%) laboratories from 18 European countries. The biosafety procedures were heterogeneous. The workload in clinical and molecular pathology decreased dramatically by 31% (range, 3%-55%) and 26% (range, 7%-62%), respectively. According to the professional category, between 28% and 41% of the staff members were not present in the laboratories but did teleworking. A total of 70% of the laboratories developed virtual meetings for the training of residents and junior pathologists. During the period of study, none of the staff members with confirmed COVID-19 became infected as a result of handling samples. CONCLUSIONS: The COVID-19 pandemic has had a strong impact on most of the European pathology laboratories included in this study. Urgent implementation of several changes to the organization of most of these laboratories, notably to better harmonize biosafety procedures, was noted at the onset of the pandemic and maintained in the event of a new wave of infection occurring in Europe.

Taking a seat at the table: an educational model for nursing empowerment.

BACKGROUND: The human resources for health crisis has generated much debate as to the radical changes necessary to mitigate the risks to universal health coverage. Nurses can make a significant impact on global health, if only they feel empowered to take their seat at the political table. AIM: The aim of this paper was to outline nurse-led initiatives to enhance organizational culture and clinical processes at the Combined Military Hospital in Rawalpindi, Pakistan. These have been designed and implemented by the United Kingdom (UK) Defence Medical Services to empower the nursing workforce in Pakistan. OUTCOME: An educational model has been developed that will build capacity, within a workforce constrained by numbers, by bridging the gap between nursing theory and practice. It is geared to actively engage Pakistani nurses in quality improvement to ensure care is based on best evidence that will enhance patient outcomes. CONCLUSION AND IMPLICATIONS FOR NURSING & HEALTH POLICY: The wider impact of the model has already been evidenced by nurses, country-wide, who are gaining the necessary skills and confidence to realize their true potential in influencing the patient care pathway and future policy. This is crucial to the recruitment and retention of nurses who might otherwise seek alternative career paths if they lack a sense of value within the profession. Their renewed sense of value will enable them to find their voice and ability to contribute to the sustainable development goals adopted by the United Nations General Assembly in 2015.

Correction: Investigation of common, low-frequency and rare genome-wide variation in anorexia nervosa.

The fortieth author's name was listed incorrectly. The correct presentation is A Keski-Rahkonen.

Professional occupation and the risk of Parkinson's disease.

BACKGROUND AND PURPOSE: Creativity in Parkinson's disease (PD) is strongly related to dopaminergic activity and medication. We hypothesized that patients with PD, including those who are in the pre-diagnostic phase of PD, are prone to choose highly structured 'conventional' professional occupations and avoid highly creative 'artistic' occupations. METHODS: At baseline of the population-based Rotterdam Study, we asked 12 147 individuals aged ≥45 years about their latest occupation and categorized occupations according to the RIASEC model. Participants underwent baseline and follow-up (median 11 years) examinations for PD. We determined associations of artistic (versus any other occupation) and conventional (versus any other occupation) occupations with PD. Additionally, we pooled our results with a recently published case-control study (Radboud Study). RESULTS: At baseline, conventional occupations were common [n = 4356 (36%)], whereas artistic occupations were rare [n = 137 (1%)]. There were 217 patients with PD, including 91 with prevalent PD and 126 with incident PD. The risk of PD varied substantially across occupational categories (chi-square, 14.61; P = 0.01). The penalized odds ratio (OR) of artistic occupations for PD was 0.19 [95% confidence interval (CI), 0.00-1.31; P = 0.11], whereas the OR of conventional occupations for PD was 1.23 (95% CI, 0.95-1.66; P = 0.10). The direction and magnitude of ORs were similar in cross-sectional and longitudinal subsamples. Pooled ORs across the Rotterdam and Radboud Studies were 0.20 (95% CI, 0.08-0.52; P < 0.001) for artistic and 1.23 (95% CI, 0.92-1.67; P = 0.08) for conventional occupations. CONCLUSIONS: The risk of PD varies substantially by choice of professional occupation. Our findings suggest that dopaminergic degeneration affects choice of occupation, which may start in the pre-diagnostic phase of PD.

Development of a prediction model for future risk of radiographic hip osteoarthritis.

OBJECTIVE: To develop and validate a prognostic model for incident radiologic hip osteoarthritis (HOA) and determine the value of previously identified predictive factors. DESIGN: We first validated previously reported predictive factors for HOA by performing univariate and multivariate analyses for all predictors in three large prospective cohorts (total sample size of 4548 with 653 incident cases). The prognostic model was developed in 2327 individuals followed for 10 years from the Rotterdam Study-I (RS-I) cohort. External validation of the model was tested on discrimination in two other cohorts: RS-II (n = 1435) and the Cohort Hip and Cohort Knee (CHECK) study (n = 786). RESULTS: From the total number of 28 previously reported predictive factors, we were able to replicate 13 factors, while 15 factors were not significantly predictive in a meta-analysis of the three cohorts. The basic model including the demographic, questionnaire, and clinical examination variables (area under the receiver-operating characteristic curve (AUC) = 0.67) or genetic markers (AUC = 0.55) or urinary C-terminal cross-linked telopeptide of type II collagen (uCTX-II) levels (AUC = 0.67) alone were poor predictors of HOA in all cohorts. Imaging factors showed the highest predictive value for the development of HOA (AUC = 0.74). Addition of imaging variables to the basic model led to substantial improvement in the discriminative ability of the model (AUC = 0.78) compared with uCTX-II (AUC = 0.74) or genetic markers (AUC = 0.68). Applying external validation, similar results were observed in the RS-II and the CHECK cohort. CONCLUSIONS: The developed prediction model included demographic, a limited number of questionnaire, and imaging risk factors seems promising for prediction of HOA.

Physical Activity Types and Health-Related Quality of Life among Middle-Aged and Elderly Adults: The Rotterdam Study.

OBJECTIVES: Physical activity (PA) is associated with health-related quality of life (HRQL). The specific PA types that provide beneficial effects in an older population remain unclear. We assessed the association of total PA, walking, cycling, domestic work, sports and gardening with HRQL in middle-aged and elderly adults. DESIGN: Cross-sectional study. SETTING: Rotterdam, the Netherlands. PARTICIPANTS: 5,554 participants, with a mean age of 69 years. MEASUREMENTS: Total PA was categorized in five groups to evaluate the dose-response effect of PA and specific PA types were categorized in tertiles. HRQL was measured with the EuroQoL 5-dimension. The outcome of every HRQL domain (i.e. mobility, self-care, daily activities, pain and mood) was expressed as having any problems versus not having problems. Logistic and linear regression analyses were used, adjusting for confounders, to examine associations of total PA and PA types with HRQL domains. RESULTS: In both middle-aged (<65 years) and elderly adults (>65 years), we found a dose-response association between total PA and better HRQL (i.e. lower odds of having problems in HRQL domains). In the middle-aged, sports was the only PA type associated with lower odds of having problems with all HRQL domains. In the elderly, all PA types were associated with less problems with HRQL domains, but cycling contributed most to the beneficial effect. CONCLUSIONS: Total PA was associated with better HRQL. Sports and cycling were the activity types that contributed most to this association in the middle-aged and elderly, respectively. Since PA levels tend to decline with aging, cycling and sports should be promoted with the aim to improve HRQL.

Impact of prediagnostic smoking and smoking cessation on colorectal cancer prognosis: a meta-analysis of individual patient data from cohorts within the CHANCES consortium.

Background: Smoking has been associated with colorectal cancer (CRC) incidence and mortality in previous studies and might also be associated with prognosis after CRC diagnosis. However, current evidence on smoking in association with CRC prognosis is limited. Patients and methods: For this individual patient data meta-analysis, sociodemographic and smoking behavior information of 12 414 incident CRC patients (median age at diagnosis: 64.3 years), recruited within 14 prospective cohort studies among previously cancer-free adults, was collected at baseline and harmonized across studies. Vital status and causes of death were collected for a mean follow-up time of 5.1 years following cancer diagnosis. Associations of smoking behavior with overall and CRC-specific survival were evaluated using Cox regression and standard meta-analysis methodology. Results: A total of 5229 participants died, 3194 from CRC. Cox regression revealed significant associations between former [hazard ratio (HR) = 1.12; 95 % confidence interval (CI) = 1.04-1.20] and current smoking (HR = 1.29; 95% CI = 1.04-1.60) and poorer overall survival compared with never smoking. Compared with current smoking, smoking cessation was associated with improved overall (HR<10 years = 0.78; 95% CI = 0.69-0.88; HR≥10 years = 0.78; 95% CI = 0.63-0.97) and CRC-specific survival (HR≥10 years = 0.76; 95% CI = 0.67-0.85). Conclusion: In this large meta-analysis including primary data of incident CRC patients from 14 prospective cohort studies on the association between smoking and CRC prognosis, former and current smoking were associated with poorer CRC prognosis compared with never smoking. Smoking cessation was associated with improved survival when compared with current smokers. Future studies should further quantify the benefits of nonsmoking, both for cancer prevention and for improving survival among CRC patients, in particular also in terms of treatment response.

Pharmacogenomics study of thiazide diuretics and QT interval in multi-ethnic populations: the cohorts for heart and aging research in genomic epidemiology.

Thiazide diuretics, commonly used antihypertensives, may cause QT interval (QT) prolongation, a risk factor for highly fatal and difficult to predict ventricular arrhythmias. We examined whether common single-nucleotide polymorphisms (SNPs) modified the association between thiazide use and QT or its component parts (QRS interval, JT interval) by performing ancestry-specific, trans-ethnic and cross-phenotype genome-wide analyses of European (66%), African American (15%) and Hispanic (19%) populations (N=78 199), leveraging longitudinal data, incorporating corrected standard errors to account for underestimation of interaction estimate variances and evaluating evidence for pathway enrichment. Although no loci achieved genome-wide significance (P<5 × 10-8), we found suggestive evidence (P<5 × 10-6) for SNPs modifying the thiazide-QT association at 22 loci, including ion transport loci (for example, NELL1, KCNQ3). The biologic plausibility of our suggestive results and simulations demonstrating modest power to detect interaction effects at genome-wide significant levels indicate that larger studies and innovative statistical methods are warranted in future efforts evaluating thiazide-SNP interactions.

Investigation of common, low-frequency and rare genome-wide variation in anorexia nervosa.

Anorexia nervosa (AN) is a complex neuropsychiatric disorder presenting with dangerously low body weight, and a deep and persistent fear of gaining weight. To date, only one genome-wide significant locus associated with AN has been identified. We performed an exome-chip based genome-wide association studies (GWAS) in 2158 cases from nine populations of European origin and 15 485 ancestrally matched controls. Unlike previous studies, this GWAS also probed association in low-frequency and rare variants. Sixteen independent variants were taken forward for in silico and de novo replication (11 common and 5 rare). No findings reached genome-wide significance. Two notable common variants were identified: rs10791286, an intronic variant in OPCML (P=9.89 × 10-6), and rs7700147, an intergenic variant (P=2.93 × 10-5). No low-frequency variant associations were identified at genome-wide significance, although the study was well-powered to detect low-frequency variants with large effect sizes, suggesting that there may be no AN loci in this genomic search space with large effect sizes.

A rare missense variant in RCL1 segregates with depression in extended families.

Depression is the most prevalent psychiatric disorder with a complex and elusive etiology that is moderately heritable. Identification of genes would greatly facilitate the elucidation of the biological mechanisms underlying depression, however, its complex etiology has proved to be a major bottleneck in the identification of its genetic risk factors, especially in genome-wide association-like studies. In this study, we exploit the properties of a genetic isolate and its family-based structure to explore whether relatively rare exonic variants influence the burden of depressive symptoms in families. Using a multistep approach involving linkage and haplotype analyses followed by exome sequencing in the Erasmus Rucphen Family (ERF) study, we identified a rare (minor allele frequency (MAF)=1%) missense c.1114C>T mutation (rs115482041) in the RCL1 gene segregating with depression across multiple generations. Rs115482041 showed significant association with depressive symptoms (N=2393, ßT-allele=2.33, P-value=1 × 10-4) and explained 2.9% of the estimated genetic variance of depressive symptoms (22%) in ERF. Despite being twice as rare (MAF<0.5%), c.1114C>T showed similar effect and significant association with depressive symptoms in samples from the independent population-based Rotterdam study (N=1604, ßT-allele=3.60, P-value=3 × 10-2). A comparison of RCL1 expression in human and mouse brain revealed a striking co-localization of RCL1 with the layer 1 interlaminar subclass of astrocytes found exclusively in higher-order primates. Our findings identify RCL1 as a novel candidate gene for depression and offer insights into mechanisms through which RCL1 may be relevant for depression.

Genes and pathways underlying susceptibility to impaired lung function in the context of environmental tobacco smoke exposure.

BACKGROUND: Studies aiming to assess genetic susceptibility for impaired lung function levels upon exposure to environmental tobacco smoke (ETS) have thus far focused on candidate-genes selected based on a-priori knowledge of potentially relevant biological pathways, such as glutathione S-transferases and ADAM33. By using a hypothesis-free approach, we aimed to identify novel susceptibility loci, and additionally explored biological pathways potentially underlying this susceptibility to impaired lung function in the context of ETS exposure. METHODS: Genome-wide interactions of single nucleotide polymorphism (SNP) by ETS exposure (0 versus ≥1 h/day) in relation to the level of forced expiratory volume in one second (FEV1) were investigated in 10,817 subjects from the Dutch LifeLines cohort study, and verified in subjects from the Swiss SAPALDIA study (n = 1276) and the Dutch Rotterdam Study (n = 1156). SNP-by-ETS exposure p-values obtained from the identification analysis were used to perform a pathway analysis. RESULTS: Fourty Five SNP-by-ETS exposure interactions with p-values <10-4 were identified in the LifeLines study, two being replicated with nominally significant p-values (<0.05) in at least one of the replication cohorts. Three pathways were enriched in the pathway-level analysis performed in the identification cohort LifeLines, i.E. the apoptosis, p38 MAPK and TNF pathways. CONCLUSION: This unique, first genome-wide gene-by-ETS interaction study on the level of FEV1 showed that pathways previously implicated in chronic obstructive pulmonary disease (COPD), a disease characterized by airflow obstruction, may also underlie susceptibility to impaired lung function in the context of ETS exposure.

Occurrence of metachronous basal cell carcinomas: a prognostic model.

BACKGROUND: A third of patients with a first basal cell carcinoma (BCC) will develop subsequent (metachronous) BCCs. OBJECTIVES: To study the prognostic effect of the number of previous BCC diagnosis dates a patient has experienced to derive a prediction model to assess the risk of metachronous BCCs that may inform individualized decision making on surveillance. METHODS: We considered participants of north-western European ancestry from a prospective population-based cohort study (Rotterdam Study). After linkage with the Dutch Pathology Registry, 1077 patients with a first BCC were included. Candidate predictors for metachronous BCCs included patient, lifestyle and tumour characteristics. The prognostic model was developed with Fine and Gray regression analysis to account for competing risk of death. We used bootstrapping to correct for within-patient correlation and statistical optimism in predictive performance. RESULTS: Second to fifth BCCs occurred in 293, 122, 58 and 36 patients, with median follow-up times of 3·0, 2·1, 1·7 and 1·8 years after the previous BCC, respectively. The risk of a new BCC was higher for patients with more metachronous BCCs. Having more than one BCC at diagnosis was another strong predictor of metachronous BCCs. Discriminative ability of the model was reasonable with an optimism-corrected c-index of 0·70 at 3 years. CONCLUSIONS: The number of previous BCC diagnosis dates was a strong prognostic factor and should be considered when predicting the risk of metachronous BCCs. When the number of previous BCC diagnosis dates is combined with other readily available characteristics into a prognostic model, patients at high risk of a new BCC can be identified.

Dietary acid load, trabecular bone integrity, and mineral density in an ageing population: the Rotterdam study.

We studied the relation between a diet that is high in acid-forming nutrients (e.g. proteins) and low in base-forming nutrients (e.g. potassium) and bone structure. We showed a negative relation, which was more prominent if proteins were of animal rather than of vegetable origin and if intake of dietary fibre was high. INTRODUCTION: Studies on dietary acid load (DAL) and fractures have shown inconsistent results. Associations between DAL, bone mineral density (BMD) and trabecular bone integrity might play a role in these inconsistencies and might be influenced by renal function and dietary fibre intake. Therefore, our aim was to study (1) associations of DAL with BMD and with the trabecular bone score (TBS) and (2) the potential influence of renal function and dietary fibre in these associations. METHODS: Dutch individuals aged 45 years and over (n = 4672) participating in the prospective cohort of the Rotterdam study were included. Based on food frequency questionnaires, three indices of DAL were calculated: the net endogenous acid production (NEAP) and the ratios of vegetable or animal protein and potassium (VegPro/K and AnPro/K). Data on lumbar spinal TBS and BMD were derived from dual-energy X-ray absorptiometry measurements. RESULTS: Independent of confounders, NEAP and AnPro/K, but not VegPro/K, were associated with low TBS (standardized ß (95%) = -0.04 (-0.07, -0.01) and -0.08 (-0.11, -0.04)) but not with BMD. Associations of AnPro/K and VegPro/K with TBS were non-linear and differently shaped. Unfavourable associations between NEAP, BMD and TBS were mainly present in subgroups with high fibre intake. CONCLUSIONS: High NEAP was associated with low TBS. Associations of AnPro/K and VegPro/K and TBS were non-linear and differently shaped. No significant associations of DAL with BMD were observed, nor was there any significant interaction between DAL and renal function. Mainly in participants with high intake of dietary fibre, DAL might be detrimental to bone.

Changes in disability in older adults with generalized radiographic osteoarthritis: A complex relationship with physical activity.

OBJECTIVE: The aim of the present study was to report on factors associated with changes in disability after 5 years, with a focus on physical activity (PA) in community-dwelling older adults with generalized radiographic osteoarthritis (GROA). METHODS: Assessment of GROA (hand, knee, hip) and disability (Health Assessment Questionnaire) in the Rotterdam Study (cohort RS-1, N = 7,983; with GROA, n = 821). A good outcome at follow-up was defined as improved or mild disability, and a poor outcome as worsened or severe disability. Factors potentially associated with outcome were demographics, joint complaints, other chronic health problems or limitations (body mass index, number of chronic conditions, cognition), and level of different types of PA. Some of these assessments were repeated in between 1997 and 1999 (RS-3), and between 2002 and 2004 (RS-4). RESULTS: A total of 309 older adults with GROA and valid measures on RS-3 and RS-4 showed mild to moderate disability, with minor increases over 5 years (follow-up N = 287 RS-3 to RS-4). PA levels decreased with increasing disability, especially in sport and walking. PA was univariately associated with a better outcome at follow-up but when adjusted for other factors (higher age, having knee pain and stiffness, and having more than two other chronic conditions) was associated with negative changes in general and lower limb disability, although not with upper limb disability. CONCLUSIONS: This was the first study to report that community-dwelling older adults with GROA show moderate levels of disability, and that reduced levels of disability are associated with higher levels of PA, but when adjusted for other confounders this association is lost. Further research is needed to study the complex relationships between PA and other determinants of disability.

Subjective measures of health and all-cause mortality - the Rotterdam Study.

BACKGROUND: Subjectively assessed health is related to mortality. Various subjective indicators of health have been studied, but it is unclear whether perceived physical functioning or mental health best accounts for the relation with mortality. METHOD: We studied the relation of subjective measures of health with all-cause mortality in 5538 participants of age 55 to 96 years at baseline from the Rotterdam Study. Various instruments of subjectively assessed health were used, that included basic activities of daily living (BADL), instrumental activities of daily living (IADL), quality of life (QoL), positive affect, somatic symptoms and negative affect. All participants completed questionnaires for each subjective measure of health and were followed for mortality for a mean of 12.2 (s.e. = 0.09) years. Cox regression analysis was conducted in the total sample. RESULTS: In this cohort, 2021 persons died during 48 534 person-years of follow-up. All measures of subjective health were related to mortality after adjusting for age, gender, education, cognition, prevalent chronic diseases and cardiovascular risk [BADL hazard ratio (HR, calculated per Z-score) = 1.35, 95% confidence interval (CI) 1.29-1.41; IADL HR = 1.27, 95% CI 1.22-1.32; QoL HR = 0.85, 95% CI 0.81-0.89; positive affect HR = 0.92, 95% CI 0.88-0.96; somatic symptoms HR = 1.11, 95% CI 1.06-1.16; and negative affect HR = 1.05, 95% CI 1.01-1.10]. In the mutually adjusted model, only BADL (HR = 1.24, 95% CI 1.16-1.32) and IADL (HR = 1.10, 95% CI 1.04-1.17) remained independently associated with mortality. CONCLUSIONS: Measures of subjectively assessed health are important indicators of mortality. Our study shows that of the different measures of subjective health, perceived physical health predicts mortality over and above mental health. Conversely, the association between mental health and mortality may partly be explained by poor perceived physical health.

Vitamin D serum levels are cross-sectionally but not prospectively associated with late-life depression.

OBJECTIVE: The evidence for a prospective association of vitamin D deficiency with the occurrence of late-life depression is limited. We aimed to study the long-term association between vitamin D serum levels and depression in a large population-based study of older adults. METHOD: We included 3251 participants from the Rotterdam Study, aged 55 and older with 32 400 person-years follow-up for depression. Baseline 25-hydroxyvitamin D (25(OH)D) serum levels were analyzed continuously and categorically. Repeated depressive symptoms' questionnaire assessments were used to assess the change of depressive symptoms. Semistructured psychiatric interviews, and GP records were used to assess incident major depressive disorder according to DSM-IV criteria. RESULTS: Low serum vitamin D levels were cross-sectionally associated with more depressive symptoms. However, low 25(OH)D serum levels were not prospectively associated with change of depressive symptoms (unstandardized beta = 0.02, 95% CI = -0.23; 0.26) or incident MDD (hazard ratio = 0.95, 95% CI = 0.86; 1.05). CONCLUSION: We observed a cross-sectional but no prospective association between serum vitamin D levels and depression. A cross-sectional association in the absence of the longitudinal association can mostly be attributed to reverse causality or residual confounding. Probably, vitamin D deficiency is not an independent risk factor for depression but co-occurs with late-life depression.

Cortical abnormalities in adults and adolescents with major depression based on brain scans from 20 cohorts worldwide in the ENIGMA Major Depressive Disorder Working Group.

The neuro-anatomical substrates of major depressive disorder (MDD) are still not well understood, despite many neuroimaging studies over the past few decades. Here we present the largest ever worldwide study by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Major Depressive Disorder Working Group on cortical structural alterations in MDD. Structural T1-weighted brain magnetic resonance imaging (MRI) scans from 2148 MDD patients and 7957 healthy controls were analysed with harmonized protocols at 20 sites around the world. To detect consistent effects of MDD and its modulators on cortical thickness and surface area estimates derived from MRI, statistical effects from sites were meta-analysed separately for adults and adolescents. Adults with MDD had thinner cortical gray matter than controls in the orbitofrontal cortex (OFC), anterior and posterior cingulate, insula and temporal lobes (Cohen's d effect sizes: -0.10 to -0.14). These effects were most pronounced in first episode and adult-onset patients (>21 years). Compared to matched controls, adolescents with MDD had lower total surface area (but no differences in cortical thickness) and regional reductions in frontal regions (medial OFC and superior frontal gyrus) and primary and higher-order visual, somatosensory and motor areas (d: -0.26 to -0.57). The strongest effects were found in recurrent adolescent patients. This highly powered global effort to identify consistent brain abnormalities showed widespread cortical alterations in MDD patients as compared to controls and suggests that MDD may impact brain structure in a highly dynamic way, with different patterns of alterations at different stages of life.

Exome-sequencing in a large population-based study reveals a rare Asn396Ser variant in the LIPG gene associated with depressive symptoms.

Despite a substantial genetic component, efforts to identify common genetic variation underlying depression have largely been unsuccessful. In the current study we aimed to identify rare genetic variants that might have large effects on depression in the general population. Using high-coverage exome-sequencing, we studied the exonic variants in 1265 individuals from the Rotterdam study (RS), who were assessed for depressive symptoms. We identified a missense Asn396Ser mutation (rs77960347) in the endothelial lipase (LIPG) gene, occurring with an allele frequency of 1% in the general population, which was significantly associated with depressive symptoms (P-value=5.2 × 10-08, ß=7.2). Replication in three independent data sets (N=3612) confirmed the association of Asn396Ser (P-value=7.1 × 10-03, ß=2.55) with depressive symptoms. LIPG is predicted to have enzymatic function in steroid biosynthesis, cholesterol biosynthesis and thyroid hormone metabolic processes. The Asn396Ser variant is predicted to have a damaging effect on the function of LIPG. Within the discovery population, carriers also showed an increased burden of white matter lesions (P-value=3.3 × 10-02) and a higher risk of Alzheimer's disease (odds ratio=2.01; P-value=2.8 × 10-02) compared with the non-carriers. Together, these findings implicate the Asn396Ser variant of LIPG in the pathogenesis of depressive symptoms in the general population.