Major depressive disorder (MDD) is a common complex trait with enormous public health significance. As part of the Genetic Association Information Network (GAIN) initiative of the US Foundation for the National Institutes of Health, we conducted a genomewide association study of 435,291 SNPs genotyped in 1,738 MDD cases and 1,802 controls selected to be at low liability for MDD. Eleven of the top 200 signals localized to a 167 kb region overlapping the gene piccolo (PCLO, whose protein product localizes to the cytomatrix of the presynaptic active zone and plays an important role in monoaminergic neurotransmission in the brain) with p-values of 7.7×10−7 for rs2715148 and 1.2×10−6 for rs2522833. We undertook replication of SNPs in this region in 5 independent samples (6,079 MDD independent cases and 5,893 controls) but no SNP exceeded the replication significance threshold when all replication samples were analyzed together. However, there was heterogeneity in the replication samples, and secondary analysis of the original sample with the sample of greatest similarity yielded p=6.4×10−8 for the non-synonymous SNP rs2522833 that gives rise to a serine to alanine substitution near a C2 calcium-binding-domain of the PCLO protein. With the integrated replication effort, we present a specific hypothesis for further studies.

The hypothesis that the S allele of the 5-HTTLPR serotonin transporter promoter region is associated with increased risk of depression, but only in individuals exposed to stressful situations, has generated much interest, research, and controversy since first proposed in 2003. Multiple meta-analyses combining results from heterogeneous analyses have not settled the issue. To determine the magnitude of the interaction and the conditions under which it might be observed, we performed new analyses on 31 datasets containing 38 802 European-ancestry subjects genotyped for 5-HTTLPR and assessed for depression and childhood maltreatment or other stressful life events, and meta-analyzed the results. Analyses targeted two stressors (narrow, broad) and two depression outcomes (current, lifetime). All groups that published on this topic prior to the initiation of our study and met the assessment and sample size criteria were invited to participate. Additional groups, identified by consortium members or self-identified in response to our protocol (published prior to the start of analysis1) with qualifying unpublished data were also invited to participate. A uniform data analysis script implementing the protocol was executed by each of the consortium members. Our findings do not support the interaction hypothesis. We found no subgroups or variable definitions for which an interaction between stress and 5-HTTLPR genotype was statistically significant. In contrast, our findings for the main effects of life stressors (strong risk factor) and 5-HTTLPR genotype (no impact on risk) are strikingly consistent across our contributing studies, the original study reporting the interaction, and subsequent meta-analyses. Our conclusion is that if an interaction exists in which the S allele of 5-HTTLPR increases risk of depression only in stressed individuals, then it is not broadly generalizable, but must be of modest effect size and only observable in limited situations.

Early literacy and language skills of twin children in the USA, Australia, and Scandinavia were explored in a genetically sensitive design (maximum N = 615 pairs). For this article, we report aspects of preschool and Grade 2 data. In Grade 2, there were strong genetic influences on word reading, reading comprehension, and spelling. Vocabulary was about equally affected by genes and shared environment. Multivariate analyses indicated substantial genetic overlap among the Grade 2 literacy variables. Longitudinal analyses showed that genetic factors evident at the preschool stage continued to affect literacy and vocabulary three years later in Grade 2, but there was also evidence of new genetic factors coming into play over the time interval, at least for literacy. Suggestions are made about the search for underlying biological and cognitive processes, and educational implications are explored.

Studies using the classical twin design often conclude that most genetic variation underlying personality is additive in nature. However, studies analyzing only twins are very limited in their ability to detect non-additive genetic variation and are unable to detect sources of variation unique to twins, which can mask non-additive genetic variation. The current study assessed 9672 MZ and DZ twin individuals and 3241 of their siblings to investigate the environmental and genetic architecture underlying eight dimensions of personality: four from Eysenck's Personality Questionnaire and four from Cloninger's Temperament and Character Inventory. Broad-sense heritability estimates from best-fitting models were two to three times greater than the narrow-sense heritability estimates for Harm Avoidance, Novelty Seeking, Reward Dependence, Persistence, Extraversion, and Neuroticism. This genetic non-additivity could be due to dominance, additive-by-additive epistasis, or to additive genetic effects combined with higher-order epistasis. Environmental effects unique to twins were detected for both Lie and Psychoticism but accounted for little overall variation. Our results illustrate the increased sensitivity afforded by extending the classical twin design to include siblings, and may provide clues to the evolutionary origins of genetic variation underlying personality.

The diathesis-stress theory for depression states that the effects of stress on the depression risk are dependent on the diathesis or vulnerability, implying multiplicative interactive effects on the liability scale. We used polygenic risk scores for major depressive disorder (MDD) calculated from the results of the most recent analysis from the Psychiatric Genomics Consortium as a direct measure of the vulnerability for depression in a sample of 5 221 individuals from 3 083 families. In the same we also had measures of stressful life events and social support and a depression symptom score, as well as DSM-IV MDD diagnoses for most individuals. In order to estimate the variance in depression explained by the genetic vulnerability, the stressors and their interactions, we fitted linear mixed models controlling for relatedness for the whole sample as well as stratified by sex. We show a significant interaction of the polygenic risk scores with personal life events (0.12% of variance explained, p-value=0.0076) contributing positively to the risk of depression. Additionally, our results suggest possible differences in the aetiology of depression between women and men. In conclusion, our findings point to an extra risk for individuals with combined vulnerability and high number of reported personal life events beyond what would be expected from the additive contributions of these factors to the liability for depression, supporting the multiplicative diathesis-stress model for this disease.

T he classical twin design (CTD) is the most common method used to infer genetic and environmental causes of phenotypic variation. As has long been acknowledged, different combinations of the common environment/assortative mating, and additive, dominant, and epistatic genetic effects can lead to the same observed covariation between twin pairs, meaning that there is an inherent indeterminacy in parameter estimates arising from the CTD. The CTD circumvents this indeterminacy by assuming that higher-order epistasis is negligible and that the effects of either dominant genetic variation or the common environment are nonexistent. These assumptions, however, lead to consistent biases in parameter estimation. The current paper quantifies these biases and discusses alternative strategies for dealing with parameter indeterminacy in twin designs. One strategy is to model the similarity among other relatives in addition to twins (extended twin-family designs), which reduces but does not eliminate indeterminacy in parameter estimates. A more general strategy, applicable to all twin designs, is to present the parameter indeterminacy explicitly, as in a graph. Presenting the space of mathematically equally likely parameter values is important, not only because it aids the proper interpretation of twin design findings, but also because it keeps behavioral geneticists themselves mindful of methodological assumptions that can easily go unexamined.

Background:The length polymorphism repeat in the promoter region of the serotonin transporter gene (5HTTLPR) is one of the most studied polymorphisms for association with a range of psychiatric and personality phenotypes. However, the original 5HTTLPR assay is prone to bias toward short allele calling.

Genetic and environmental relations between vocabulary and reading skills were explored longitudinally from preschool through grades 2 and 4. At preschool there were strong shared-environment and weak genetic influences on both vocabulary and print knowledge, but substantial differences in their source. Separation of etiology for vocabulary and reading continued for word recognition and decoding through grade 4, but genetic and environmental correlations between vocabulary and reading comprehension approached unity by grade 4, when vocabulary and word recognition accounted for all of the genetic and shared environment influences on reading comprehension.