The associations between social support and depression, and between stress and depression have been the subject of considerable research, and although this has included longitudinal designs, these have rarely controlled for genetic effects that mediate these associations. The sample comprised 7,356 female and 4,882 male participants aged 18-95 from the Australian NHMRC Twin Registry (ATR). Of these, between 100 and 324 female pairs and between 41 and 169 male pairs, depending on the measure, were monozygotic (MZ) pairs discordant for depression. We use the co-twin control design in combination with prospective analyses to explore the association between a composite of predictors (perceived social support, stress, and support × stress) and depression. With familial effects included, both perceived support and stress were antecedents to, and sequelae of, depression, but no stress-buffering occurred. With familial effects controlled, stress was a sequela of a prior depressive episode, and neither lack of support nor stress were antecedents to depression, though their interaction approached significance for males. The male twin who later became depressed had previously reported lower perceived support in the face of multiple stressors compared to his co-twin who did not become depressed. We show that associations commonly observed with prospective designs are partly due to familial factors.

Major depressive disorder (MDD) is a common complex trait with enormous public health significance. As part of the Genetic Association Information Network initiative of the US Foundation for the National Institutes of Health, we conducted a genome-wide association study of 435 291 single nucleotide polymorphisms (SNPs) genotyped in 1738 MDD cases and 1802 controls selected to be at low liability for MDD. Of the top 200, 11 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 is important 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 five independent samples (6079 MDD independent cases and 5893 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 nonsynonymous 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.

In this article we report on reading ability of twin children in kindergarten to Grade 2 as a function of whether members of the pairs are assigned to the same or different classrooms. All analyses were run using mixed model regressions to account for the interdependence between twin pairs. The samples, total N = 1505, are from Australia and the United States. We found a close-to-significant difference in favor of same-class children in kindergarten and Grade 1. However, when results were adjusted to take account of pre-existing differences in disruptive behavior and in preliteracy ability, the class assignment effects disappeared. We suggest that these pre-existing differences, particularly disruptive behavior, are influencing decisions about whether to separate twins or not and also affecting early reading performance, a conclusion supported by significant correlations between the behavioral measures, preliteracy, and school-based reading. We conclude that, on average, early literacy in twins is not directly affected by their assignment to the same or different classrooms.

The 'classical twin design' (CTD) circumvents parameter indeterminacy by assuming (1) negligible higher-order epistasis; and (2) either nonadditive genetic or common environmental effects are nonexistent, creating two potential sources of bias (Eaves et al., 1978; Grayson, 1989). Because the extended 'twin-family design' (ETFD) uses many more unique covariance observations to estimate parameters, common environmental and nonadditive genetic parameters can be simultaneously estimated. The ETFD thereby corrects for what is likely to be the largest of the two sources of bias in CTD parameter estimates (Keller & Coventry, 2005). In the current paper, we assess the extent of this and other potential sources of bias in the CTD by comparing all published ETFD parameter estimates to CTD parameter estimates derived from the same data. CTD estimates of the common environment were lower than ETFD estimates of the common environment for some phenotypes, but for other phenotypes (e.g., stature in females and certain social attitudes), what appeared as the common environment was resolved to be assortative mating in the ETFD. On average, CTD estimates of nonadditive genetic factors were 43% lower, and additive genetic factors 63% higher, than ETFD estimates. However, broad-sense heritability estimates from the CTD were only 18% higher than ETFD estimates, highlighting that the CTD is useful for estimating broad-sense but not narrow-sense heritability. These results suggest that CTD estimates can be misleading when interpreted literally, but useful, albeit coarse, when interpreted properly.

Background: The positive health and well-being effects of social support have been consistently demonstrated in the literature since the late 1970s. However, a better understanding of the effects of age and sex is required. Method: We examined the factor structure and reliability of Kesslers Perceived Social Support (KPSS) measure in a community–based sample that comprised younger and older adult cohorts from the Australian Twin Registry (ATR), totalling 11,389 males and females aged 18–95, of whom 887 were retested 25 months later. Results: Factor analysis consistently identified seven factors: support from 'spouse, twin, children, parents, relatives, friends' and 'helping' support. Internal reliability for the seven dimensions ranged from 0.87 to 0.71 and test–retest reliability ranged from 0.75 to 0.48. Perceived support was only marginally higher in females. Age dependencies were explored. Across the age range, there was a slight decline (more marked in females) in the perceived support from spouse, parent and friend, a slight increase in perceived relative and helping support for males but none for females, a substantial increase in the perceived support from children for males and females and a negligible decline in total KPSS for females against a negligible increase for males. The perceived support from twin remained constant. Females were more likely to have a confidant, although this declined with age whilst increasing with age for males. Conclusions: Total scores for perceived social support conflate heterogeneous patterns on sub–scales that differ markedly by age and sex. Our paper describes these relationships in detail in a very large Australian sample.

We examine the interaction between stressful life events (SLE) and genotypes for the length polymorphism of the serotonin receptor gene (SHTTLPR) on risk of depression. We hypothesize that if the interaction is real, monozygotic twin pairs (MZT) homozygous for the short allele (SS) will have a greater within pair variance In depression measures than MZT homozygous for the long allele (LL), as a reflection of their increased sensitivity to unknown environmental risk factors. Telephone interviews were used to assess symptoms of depression and suicidality on 824 MZT. Rather than using the interview items to calculate sum scores or allocate diagnostic classes we use Item Response Theory to model the contribution of each item to each individual's underlying liability to depression. SLE were also measured on the MZT assessed by mailed questionnaire on average 3.8 years previously, and these were used in follow-up analyses. We find no evidence for significant differences in within pair variance between 5HTTLPR genotypic classes and so can provide no support for interaction between these genotypes and the environment. The use of MZT provides a novel framework for examining genotype X environment interaction in the absence of measures on SLE.

It is well established that major depressive disorder (MDD) is partly heritable. We present a genome-wide linkage study aiming to find regions on the genome that influence the vulnerability for MDD. Our sample consists of 110 Australian and 23 Dutch pedigrees with two or more siblings affected with MDD (total N = 278). Linkage analysis was carried out in MERLIN. Three regions showed suggestive linkage signals. The highest LOD-score of 2.1 was found on chromosome 17 at 52.6 cM along with LOD scores of 1.9 and 1.7 on chromosome 8 at 2.7 cM and chromosome 2 at 90.6 cM, respectively. The result on chromosome 8 seems most promising as two previous studies also found linkage in this region, once suggestive and once significant. The linkage peak on chromosome 17 harbors the serotonin transporter gene. In the Australian and Dutch sample, the serotonin transporter length polymorphism did not show evidence for association, thus other genes in this region or other polymorphisms in the serotonin transporter gene might be associated with MDD. Further replication is needed to establish the relevance of our linkage finding on chromosome 2.

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 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.

To date, research shows that the genetic etiology of reading disability is not dissimilar to that observed for the normal range, supporting the generalist genes hypothesis (Plomin and Kovas 2005). However, findings on the genetic etiology of reading disability in boys versus girls are mixed. Some observe greater heritability in boys (Harlaar et al. 2005; Stevenson 1992), while others do not (Wadsworth and DeFries 2005). We explored these issues for reading measured with the TOWRE at Grade 1 with a dataset compiled across Australia and the US. The full distribution of the sample comprised 413 MZs and 420 DZs. The top and bottom probands were those with scores greater than 1 SD either above or below the mean. For the bottom proband, the estimates of A, D, C and E were 53, 0, 26 and 21%; for the full distribution they were 77, 0, 7 and 16%; and for the top proband they were 72, 17, 0 and 11%. Through not significant, this shows a trend whereby, when explaining differences between high end reading ability and the normal range, genetic effects were more important, but when explaining differences between reading disability and the normal range, environmental effects played more of a role. While inconsistent with previous research, our trend may be from detrimental environmental effects that impact low but not high end reading ability, rather than differential genetic effects, so our results are not inconsistent with the generalist genes hypothesis. An analysis of the bottom proband separately for males and females showed slightly stronger genetic effects in males (effects of A, C and E were 45, 21 and 24%) than females (effects of A, C and E were 63, 21 and 16%). These differences were not significant thought were in the same direction as Harlaar et al. (2005) and Stevenson (1992) but not Wadsworth and DeFries (2005).

Serotonergic neurotransmission impacts on a wide range of behaviors, including cognition and emotion (1,2), and drugs targeting serotonin reuptake are clinically effective antidepressants (3). As a result, one of the most studied polymorphisms for association with a broad range of psychiatric and personality phenotypes is the length polymorphism repeat (LPR) in the promoter region of the serotonin transporter gene (5HTT renamed SLC6A4) (5HTTLPR). The 5HTTLPR polymorphism comprises a 43-base pair (bp) (4–8) insertion or deletion (long, "L," with 16 repeat units or short, "S," with 14 repeat units, alleles, respectively). The S allele (frequency in Caucasians ~.45 [9]) reduces transcriptional efficiency, resulting in decreased SLC6A4expression and function (10). Association studies and subsequent meta-analyses (Table 1) (11–15) have shown conflicting results in support of an association between the S allele and anxiety, depression, and the personality trait neuroticism (a measure of emotional stability that is genetically correlated to both anxiety and depression [16–18]). Conflicting results have dogged candidate gene association studies for many complex disorders, attributable to small sample sizes of both primary and replication studies, heterogenous subject populations, association dependent on environmental conditions such as stressful life events (19), and differing instruments for assessment of phenotypic traits and statistical methods (e.g., [20,21]). However, an additional problem specific to 5HTTLPR relates to the genotyping assay, which has caused considerable bias toward S allele identification (22,23). Furthermore, association may have been compromised by the presence of an A/G single nucleotide polymorphism (SNP), rs25531, that lies within the L allele of 5HTTLPR (5,8); the L allele with the rarer G allele of rs25531 (denoted L) is functionally equivalent to the S allele because of changes to the activating protein 2 (AP2) transcription factor binding site altered by this SNP (5,8).