STUDY QUESTION: Is there an association between low-to-moderate levels of prenatal alcohol exposure (PAE) and children's facial shape? SUMMARY ANSWER: PAE before and during pregnancy, even at low level (<12 g of alcohol per week), was found associated with the facial shape of children, and these associations were found attenuated as children grow older. WHAT IS KNOWN ALREADY: High levels of PAE during pregnancy can have significant adverse associations with a child's health development resulting in recognizably abnormal facial development. STUDY DESIGN, SIZE, DURATION: This study was based on the Generation R Study, a prospective cohort from fetal life onwards with maternal and offspring data. We analyzed children 3-dimensional (3D) facial images taken at ages 9 (n = 3149) and 13 years (n = 2477) together with the data of maternal alcohol consumption. PARTICIPANTS/MATERIALS, SETTING, METHODS: We defined six levels of PAE based on the frequency and dose of alcohol consumption and defined three tiers based on the timing of alcohol exposure of the unborn child. For the image analysis, we used 3D graph convolutional networks for non-linear dimensionality reduction, which compressed the high-dimensional images into 200 traits representing facial morphology. These 200 traits were used for statistical analysis to search for associations with PAE. Finally, we generated heatmaps to display the facial phenotypes associated with PAE. MAIN RESULTS AND THE ROLE OF CHANCE: The results of the linear regression in the 9-year-old children survived correction for multiple testing with false discovery rate (FDR). In Tier 1 where we examined PAE only before pregnancy (exposed N = 278, unexposed N = 760), we found three traits survived FDR correction. The lowest FDR-P is 1.7e-05 (beta = 0.021, SE = 0.0040) in Trait #29; In Tier 2b where we examine any PAE during first trimester (exposed N = 756; unexposed N = 760), we found eight traits survived FDR correction. The lowest FDR-P is 9.0e-03 (beta = -0.013, SE = 0.0033) in Trait #139. Moreover, more statistically significant facial traits were found in higher levels of PAE. No FDR-significant results were found in the 13-year-old children. We map these significant traits back to the face, and found the most common detected facial phenotypes included turned-up nose tip, shortened nose, turned-out chin, and turned-in lower-eyelid-related regions. LIMITATIONS, REASONS FOR CAUTION: We had no data for alcohol consumption more than three months prior to pregnancy and thus do not know if maternal drinking had chronic effects. The self-reported questionnaire might not reflect accurate alcohol measurements because mothers may have denied their alcohol consumption. WIDER IMPLICATIONS OF THE FINDINGS: Our results imply that facial morphology, such as quantified by the approach we proposed here, can be used as a biomarker in further investigations. Furthermore, our study suggests that for women who are pregnant or want to become pregnant soon, should quit alcohol consumption several months before conception and completely during pregnancy to avoid adverse health outcomes in the offspring. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by Erasmus Medical Centre, Rotterdam, the Erasmus University Rotterdam, and the Netherlands Organization for Health Research. V.W.V.J. reports receipt of funding from the Netherlands Organization for Health Research (ZonMw 90700303). W.J.N. is a founder, a scientific lead, and a shareholder of Quantib BV. TRIAL REGISTRATION NUMBER: N/A.

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.

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, β=7.2). Replication in three independent data sets (N=3612) confirmed the association of Asn396Ser (P-value=7.1 × 10 -03, β=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 × 1 -02) and a higher risk of Alzheimer's disease (odds ration=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.