Alternative splicing regulates adaptor protein binding, trafficking, and activity of the Vps10p domain receptor SorCS2 in neuronal development.

The Vps10p domain receptor SorCS2 is crucial for the development and function of the nervous system and essential for brain-derived neurotrophic factor (BDNF)-induced changes in neuronal morphology and plasticity. SorCS2 regulates the subcellular trafficking of the BDNF signaling receptor TrkB as well as selected neurotransmitter receptors in a manner that is dependent on the SorCS2 intracellular domain (ICD). However, the cellular machinery and adaptor protein (AP) interactions that regulate receptor trafficking via the SorCS2 ICD are unknown. We here identify four splice variants of human SorCS2 differing in the insertion of an acidic cluster motif and/or a serine residue within the ICD. We show that each variant undergoes posttranslational proteolytic processing into a one- or two-chain receptor, giving rise to eight protein isoforms, the expression of which differs between neuronal and nonneuronal tissues and is affected by cellular stressors. We found that the only variants without the serine were able to rescue BDNF-induced branching of SorCS2 knockout hippocampal neurons, while variants without the acidic cluster showed increased interactions with clathrin-associated APs AP-1, AP-2, and AP-3. Using yeast two-hybrid screens, we further discovered that all variants bound dynein light chain Tctex-type 3; however, only variants with an acidic cluster motif bound kinesin light chain 1. Accordingly, splice variants showed markedly different trafficking properties and localized to different subcellular compartments. Taken together, our findings demonstrate the existence of eight functional SorCS2 isoforms with differential capacity for interactions with cytosolic ligands dynein light chain Tctex-type 3 and kinesin light chain 1, which potentially allows cell-type specific SorCS2 trafficking and BDNF signaling.

Disentangling potential causal effects of educational duration on well-being, and mental and physical health outcomes.

BACKGROUND: Extensive research has focused on the potential benefits of education on various mental and physical health outcomes. However, whether the associations reflect a causal effect is harder to establish. METHODS: To examine associations between educational duration and specific aspects of well-being, anxiety and mood disorders, and cardiovascular health in a sample of European Ancestry UK Biobank participants born in England and Wales, we apply four different causal inference methods (a natural policy experiment leveraging the minimum school-leaving age, a sibling-control design, Mendelian randomization [MR], and within-family MR), and assess if the methods converge on the same conclusion. RESULTS: A comparison of results across the four methods reveals that associations between educational duration and these outcomes appears predominantly to be the result of confounding or bias rather than a true causal effect of education on well-being and health outcomes. Although we do consistently find no associations between educational duration and happiness, family satisfaction, work satisfaction, meaning in life, anxiety, and bipolar disorder, we do not find consistent significant associations across all methods for the other phenotypes (health satisfaction, depression, financial satisfaction, friendship satisfaction, neuroticism, and cardiovascular outcomes). CONCLUSIONS: We discuss inconsistencies in results across methods considering their respective limitations and biases, and additionally discuss the generalizability of our findings in light of the sample and phenotype limitations. Overall, this study strengthens the idea that triangulation across different methods is necessary to enhance our understanding of the causal consequences of educational duration.

Distinguishing happiness and meaning in life from depressive symptoms: A GWAS-by-subtraction study in the UK Biobank.

Hedonic (happiness) and eudaimonic (meaning in life) well-being are negatively related to depressive symptoms. Genetic variants play a role in this association, reflected in substantial genetic correlations. We investigated the overlap and differences between well-being and depressive symptoms, using results of Genome-Wide Association studies (GWAS) in UK Biobank. Subtracting GWAS summary statistics of depressive symptoms from those of happiness and meaning in life, we obtained GWASs of respectively "pure" happiness (neffective = 216,497) and "pure" meaning (neffective = 102,300). For both, we identified one genome-wide significant SNP (rs1078141 and rs79520962, respectively). After subtraction, SNP heritability reduced from 6.3% to 3.3% for pure happiness and from 6.2% to 4.2% for pure meaning. The genetic correlation between the well-being measures reduced from 0.78 to 0.65. Pure happiness and pure meaning became genetically unrelated to traits strongly associated with depressive symptoms, including loneliness, and psychiatric disorders. For other traits, including ADHD, educational attainment, and smoking, the genetic correlations of well-being versus pure well-being changed substantially. GWAS-by-subtraction allowed us to investigate the genetic variance of well-being unrelated to depressive symptoms. Genetic correlations with different traits led to new insights about this unique part of well-being. Our results can be used as a starting point to test causal relationships with other variables, and design future well-being interventions.

Genetic Risk for Smoking: Disentangling Interplay Between Genes and Socioeconomic Status.

This study aims to disentangle the contribution of genetic liability, educational attainment (EA), and their overlap and interaction in lifetime smoking. We conducted genome-wide association studies (GWASs) in UK Biobank (N = 394,718) to (i) capture variants for lifetime smoking, (ii) variants for EA, and (iii) variants that contribute to lifetime smoking independently from EA ('smoking-without-EA'). Based on the GWASs, three polygenic scores (PGSs) were created for individuals from the Netherlands Twin Register (NTR, N = 17,805) and the Netherlands Mental Health Survey and Incidence Study-2 (NEMESIS-2, N = 3090). We tested gene-environment (G × E) interactions between each PGS, neighborhood socioeconomic status (SES) and EA on lifetime smoking. To assess if the PGS effects were specific to smoking or had broader implications, we repeated the analyses with measures of mental health. After subtracting EA effects from the smoking GWAS, the SNP-based heritability decreased from 9.2 to 7.2%. The genetic correlation between smoking and SES characteristics was reduced, whereas overlap with smoking traits was less affected by subtracting EA. The PGSs for smoking, EA, and smoking-without-EA all predicted smoking. For mental health, only the PGS for EA was a reliable predictor. There were suggestions for G × E for some relationships, but there were no clear patterns per PGS type. This study showed that the genetic architecture of smoking has an EA component in addition to other, possibly more direct components. PGSs based on EA and smoking-without-EA had distinct predictive profiles. This study shows how disentangling different models of genetic liability and interplay can contribute to our understanding of the etiology of smoking.

Evaluating the causal relationship between educational attainment and mental health.

We investigate the causal relationship between educational attainment (EA) and mental health using two research designs. First, we compare the relationship between EA and 18 psychiatric diagnoses within sibship in Dutch national registry data (N=1.7 million), thereby controlling for unmeasured familial factors. Second, we apply two-sample Mendelian Randomization, which uses genetic variants related to EA or psychiatric diagnosis as instrumental variables, to test whether there is a causal relation in either direction. Our results suggest that lower levels of EA causally increase the risk of MDD, ADHD, alcohol dependence, GAD and PTSD diagnoses. We also find evidence of a causal effect of ADHD on EA. For schizophrenia, anorexia nervosa, OCD, and bipolar disorder, results were inconsistent across the different approaches, highlighting the importance of using multiple research designs to understand complex relationships such as between EA and mental health.

The association between parental internalizing disorders and child school performance.

Parents play a crucial role in children's lives. Despite high prevalences of anxiety and depression, we do not know how these disorders among parents associate with child school performance in Norway. We use regression models to estimate associations between parental mental disorders and child school performance, while adjusting for some social and genetic confounders. Parental anxiety and depression were assessed from administrative registers of government funded health service consultations for all individuals in Norway with children born between 1992 and 2002. School performance was assessed as standardized grade point average at the end of compulsory education when children are 16 years old. Associations were also considered in samples of adoptees and among differentially affected siblings. We find that 18.8% of children have a parent with an anxiety or depression diagnosis from primary care during the last three years of compulsory education (yearly prevalence: 11.5%). There is a negative association between these parental mental disorders and child school outcomes (z = 0.43). This association was weakened, but statistically significant among differentially exposed siblings (z = 0.04), while disappearing in adoptee children. Many children experience that their parents have anxiety or depression and receive a diagnosis from primary care. On average, these children have lower school performance. The association is attenuated when comparing differentially exposed siblings and disappears in adoptee children. These results have a poor fit with the hypothesis that parental internalizing is an influential causal factor in determining children's educational success.

Genetic contributions of noncognitive skills to academic development.

Noncognitive skills such as motivation and self-regulation, predict academic achievement beyond cognitive skills. However, the role of genetic and environmental factors and of their interplay in these developmental associations remains unclear. We provide a comprehensive account of how cognitive and noncognitive skills contribute to academic achievement from ages 7 to 16 in a sample of >10,000 children from England and Wales. Results indicated that noncognitive skills become increasingly predictive of academic achievement across development. Triangulating genetic methods, including twin analyses and polygenic scores (PGS), we found that the contribution of noncognitive genetics to academic achievement becomes stronger over development. The PGS for noncognitive skills predicted academic achievement developmentally, with prediction nearly doubling by age 16, pointing to gene-environment correlation (rGE). Within-family analyses indicated both passive and active/evocative rGE processes driven by noncognitive genetics. By studying genetic effects through a developmental lens, we provide novel insights into the role of noncognitive skills in academic development.

Genetic contributions of noncognitive skills to academic development.

Noncognitive skills such as motivation and self-regulation, are partly heritable and predict academic achievement beyond cognitive skills. However, how the relationship between noncognitive skills and academic achievement changes over development is unclear. The current study examined how cognitive and noncognitive skills contribute to academic achievement from ages 7 to 16 in a sample of over 10,000 children from England and Wales. Noncognitive skills were increasingly predictive of academic achievement across development. Twin and polygenic scores analyses found that the contribution of noncognitive genetics to academic achievement became stronger over the school years. Results from within-family analyses indicated that associations with noncognitive genetics could not simply be attributed to confounding by environmental differences between nuclear families and are consistent with a possible role for evocative/active gene-environment correlations. By studying genetic effects through a developmental lens, we provide novel insights into the role of noncognitive skills in academic development.

Estimating effects of parents' cognitive and non-cognitive skills on offspring education using polygenic scores.

Understanding how parents' cognitive and non-cognitive skills influence offspring education is essential for educational, family and economic policy. We use genetics (GWAS-by-subtraction) to assess a latent, broad non-cognitive skills dimension. To index parental effects controlling for genetic transmission, we estimate indirect parental genetic effects of polygenic scores on childhood and adulthood educational outcomes, using siblings (N = 47,459), adoptees (N = 6407), and parent-offspring trios (N = 2534) in three UK and Dutch cohorts. We find that parental cognitive and non-cognitive skills affect offspring education through their environment: on average across cohorts and designs, indirect genetic effects explain 36-40% of population polygenic score associations. However, indirect genetic effects are lower for achievement in the Dutch cohort, and for the adoption design. We identify potential causes of higher sibling- and trio-based estimates: prenatal indirect genetic effects, population stratification, and assortative mating. Our phenotype-agnostic, genetically sensitive approach has established overall environmental effects of parents' skills, facilitating future mechanistic work.

Investigating the genetic architecture of noncognitive skills using GWAS-by-subtraction.

Little is known about the genetic architecture of traits affecting educational attainment other than cognitive ability. We used genomic structural equation modeling and prior genome-wide association studies (GWASs) of educational attainment (n = 1,131,881) and cognitive test performance (n = 257,841) to estimate SNP associations with educational attainment variation that is independent of cognitive ability. We identified 157 genome-wide-significant loci and a polygenic architecture accounting for 57% of genetic variance in educational attainment. Noncognitive genetics were enriched in the same brain tissues and cell types as cognitive performance, but showed different associations with gray-matter brain volumes. Noncognitive genetics were further distinguished by associations with personality traits, less risky behavior and increased risk for certain psychiatric disorders. For socioeconomic success and longevity, noncognitive and cognitive-performance genetics demonstrated associations of similar magnitude. By conducting a GWAS of a phenotype that was not directly measured, we offer a view of genetic architecture of noncognitive skills influencing educational success.

The effects of age at menarche and first sexual intercourse on reproductive and behavioural outcomes: A Mendelian randomization study.

There is substantial variation in the timing of significant reproductive life events such as menarche and first sexual intercourse. Life history theory explains this variation as an adaptive response to an individual's environment and it is important to examine how traits within life history strategies affect each other. Here we applied Mendelian randomization (MR) methods to investigate whether there is a causal effect of variation in age at menarche and age at first sexual intercourse (markers or results of exposure to early life adversity) on outcomes related to reproduction, education and risky behaviour in UK Biobank (N = 114 883-181 255). Our results suggest that earlier age at menarche affects some traits that characterize life history strategies including earlier age at first and last birth, decreased educational attainment, and decreased age at leaving education (for example, we found evidence for a 0.26 year decrease in age at first birth per year decrease in age at menarche, 95% confidence interval: -0.34 to -0.17; p < 0.001). We find no clear evidence of effects of age at menarche on other outcomes, such as risk taking behaviour. Age at first sexual intercourse was also related to many life history outcomes, although there was evidence of horizontal pleiotropy which violates an assumption of MR and we therefore cannot infer causality from this analysis. Taken together, these results highlight how MR can be applied to test predictions of life history theory and to better understand determinants of health and social behaviour.