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AbstractRecounts how our collaboration with Nick Martin was shaped over two decades, leading to the first studies of predictions from the 'Dual Route Cascaded' computational model of reading in twins, and extending into the molecular work, first linkage, fine mapping of genes identified in pedigree studies, into now the genomewide association study era and the first polygenic risk scores for reading and their potential in early clarifying causality and validating interventions, as well as for future global collaborations in improving these predictors and identifying causal variants. We highlight Nick's warm, future-focused optimism, support and inclusive approach without which none of this would have been possible. The circle of Nick asking, over half a century ago, 'What genes do you think make some kids get better grades?' has built a diverse scientific legacy involving thousands of papers and collaborations. The (heritable) traits of curiosity, boldness, warmth, interest in societally important questions, openness to new methods, ambition and collaborative skill to bring into being the infrastructure and samples needed for this research are rare, and we are grateful.

AbstractIn recent years, there has been a renewed interest in the relationship between intelligence and personality. Extraversion, in particular, has been suggested to influence intelligence, but the direction of this relationship has been controversial (Wolf & Ackerman, 2005). In a young adult sample, the NEO PI-R was completed by 103 pairs of monozygotic twins, 181 pairs of dizygotic twins and 210 of their nontwin siblings. IQ data (Multidimensional Aptitude Battery) were available for approximately three quarters of this sample, and were collected at 16 years as part of an ongoing study of cognition conducted by the Queensland Institute of Medical Research. All extraversion facets were significantly influenced by genes with both additive and nonadditive genetic effects being important (heritabilities ranged from .25 for activity to .54 for warmth). While a significant correlation between the extraversion domain score and IQ was not found, the extraversion facet of excitement-seeking (E5) was significantly negatively correlated with both verbal (r= −.15) and performance (r= −.11) IQ scores. The facet of gregariousness was significantly correlated with verbal IQ only (r= −.09). The relationship between excitement-seeking and IQ was further shown to be solely due to additive genetic influences. These common genetic effects may stem from a dependence on brain dopamine, a neurotransmitter that has been implicated in both personality and cognition.

AbstractGenetic and environmental sources of covariation among cognitive measures of verbal IQ, performance IQ (PIQ), academic achievement, 2-choice reaction time (CRT), inspection time (IT) and the 6 Openness facets of the NEO Personality Inventory-Revised (NEO PI-R) were examined. The number of twin and twin–sibling pairs ranged from 432 (182 MZ, 350 DZ/sibling) to 1023 (273 MZ, 750 DZ/sibling) for cognitive measures, and between 432 (90 MZ, 342 DZ/sibling) — 437 (91 MZ, 346 DZ/sibling) for Openness facets. Structural equation modeling best supported a model with a 3-factor additive genetic structure. A genetic general factor subsumed the 5 cognitive measures and 5 of the 6 Openness facets (Actions did not load significantly). A second additive genetic factor incorporated the 6 Openness facets, and a third additive genetic factor incorporated the 5 cognitive measures. Specific additive and dominance genetic effects were also evident, as were shared common and shared unique environmental influences, and specific unique environmental effects. The Openness facets of Ideas and Values evidenced the strongest phenotypic correlations with cognitive indices, particularly verbal measures. The genetic correlations among Openness facets and cognitive measures ranged from −.06 to .79. Results were interpreted as suggesting that Openness is related to general cognitive ability (g) through a genetic mechanism and thatgengenders a minor but discernable disposition towards Openness for the majority of facets.

AbstractThis study examined the genetic and environmental relationships among 5 academic achievement skills of a standardized test of academic achievement, the Queensland Core Skills Test (QCST; Queensland Studies Authority, 2003a). QCST participants included 182 monozygotic pairs and 208 dizygotic pairs (mean 17 years ± 0.4 standard deviation). IQ data were included in the analysis to correct for ascertainment bias. A genetic general factor explained virtually all genetic variance in the component academic skills scores, and accounted for 32% to 73% of their phenotypic variances. It also explained 56% and 42% of variation in Verbal IQ and Performance IQ respectively, suggesting that this factor is genetic g. Modest specific genetic effects were evident for achievement in mathematical problem solving and written expression. A single common factor adequately explained common environmental effects, which were also modest, and possibly due to assortative mating. The results suggest that general academic ability, derived from genetic influences and to a lesser extent common environmental influences, is the primary source of variation in component skills of the QCST.

AbstractReading difficulties are prevalent worldwide, including in economically developed countries, and are associated with low academic achievement and unemployment. Longitudinal studies have identified several early childhood predictors of reading ability, but studies frequently lack genotype data that would enable testing of predictors with heritable influences. The National Child Development Study (NCDS) is a UK birth cohort study containing direct reading skill variables at every data collection wave from age 7 years through to adulthood with a subsample (finaln= 6431) for whom modern genotype data are available. It is one of the longest running UK cohort studies for which genotyped data are currently available and is a rich dataset with excellent potential for future phenotypic and gene-by-environment interaction studies in reading. Here, we carry out imputation of the genotype data to the Haplotype Reference Panel, an updated reference panel that offers greater imputation quality. Guiding phenotype choice, we report a principal components analysis of nine reading variables, yielding a composite measure of reading ability in the genotyped sample. We include recommendations for use of composite scores and the most reliable variables for use during childhood when conducting longitudinal, genetically sensitive analyses of reading ability.

A set of 10 SNPs associated with reading ability in 7-year-olds was reported based on initial pooled analyses of 100K SNP chip data, with follow-up testing stages using pooling and individual testing. Here we examine this association in an adolescent population sample of Australian twins and siblings (N= 1177) aged 12 to 25 years. One (rs1842129) of the 10 SNPs approached significance (P= .05) but no support was found for the remaining 9 SNPs or the SNP set itself. Results indicate that these SNPs are not associated with reading ability in an Australian population. The results are interpreted as supporting use of much larger SNP sets in common disorders where effects are small.

AbstractTwin studies of diabetes mellitus can help elucidate genetic and environmental factors in etiology and can provide valuable biological samples for testing functional hypotheses, for example using expression and methylation studies of discordant pairs. We searched the volunteer Australian Twin Registry (19,387 pairs) for twins with diabetes using disease checklists from nine different surveys conducted from 1980–2000. After follow-up questionnaires to the twins and their doctors to confirm diagnoses, we eventually identified 46 pairs where one or both had type 1 diabetes (T1D), 113 pairs with type 2 diabetes (T2D), 41 female pairs with gestational diabetes (GD), 5 pairs with impaired glucose tolerance (IGT) and one pair with MODY. Heritabilities of T1D, T2D and GD were all high, but our samples did not have the power to detect effects of shared environment unless they were very large. Weight differences between affected and unaffected cotwins from monozygotic (MZ) discordant pairs were large for T2D and GD, but much larger again for discordant dizygotic (DZ) pairs. The bivariate genetic analysis (under the multifactorial threshold model) estimated the genetic correlation between body mass index (BMI) and T2D to be 0.46, and the environmental correlation at only 0.06.

AbstractReading and language abilities are critical for educational achievement and success in adulthood. Variation in these traits is highly heritable, but the underlying genetic architecture is largely undiscovered. Genetic studies of reading and language skills traditionally focus on children with developmental disorders; however, much larger unselected adult samples are available, increasing power to identify associations with specific genetic variants of small effect size. We introduce an Australian adult population cohort (41.7–73.2 years of age, N = 1505) in which we obtained data using validated measures of several aspects of reading and language abilities. We performed genetic association analysis for a reading and spelling composite score, nonword reading (assessing phonological processing: a core component in learning to read), phonetic spelling, self-reported reading impairment and nonword repetition (a marker of language ability). Given the limited power in a sample of this size (~80% power to find a minimum effect size of 0.005), we focused on analyzing candidate genes that have been associated with dyslexia and developmental speech and language disorders in prior studies. In gene-based tests, FOXP2, a gene implicated in speech/language disorders, was associated with nonword repetition (p < .001), phonetic spelling (p = .002) and the reading and spelling composite score (p < .001). Gene-set analyses of candidate dyslexia and speech/language disorder genes were not significant. These findings contribute to the assessment of genetic associations in reading and language disorders, crucial for understanding their etiology and informing intervention strategies, and validate the approach of using unselected adult samples for gene discovery in language and reading.

Acknowledgements: We thank the LBC1936 members and project staff. Study Funding: The LBC1936 and this research are supported by Age UK (Disconnected Mind project), the UK Medical Research Council [MRC; G0701120, G1001245, MR/M013111/1, MR/R024065/1], and the University of Edinburgh. SRC, MEB, and IJD were also supported by a National Institutes of Health (NIH) research grant R01AG054628. JMW, IJD are also supported by a Wellcome Trust Strategic Award (Ref 104036/Z/14/Z). MCVH is funded by the Row Fogo Charitable Trust (grant No. BROD.FID3668413). SRC was also supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant Number 221890/Z/20/Z). Imaging and image analysis was performed at the Brain Research Imaging Centre (http://www.sbirc.ed.ac.uk/), Edinburgh, supported by the Scottish Funding Council SINAPSE Collaboration. LCAC acknowledges 4 Luciano funding from the Scottish Government's Rural and Environment Science and Analytical Services (RESAS) division. MVH is funded by the Row Fogo Charitable Trust Centre for Research into Ageing and the Brain (Ref No: AD.ROW4.35. BRO-D.FID3668413). JMW received funding from the UK Dementia Research Institute which receives its funding from DRI Ltd, funded by the UK Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. ; Peer reviewed ; Publisher PDF

AbstractWe assessed the heritability of head circumference, an approximation of brain size, in twin-sib families of different ages. Data from the youngest participants were collected a few weeks after birth and from the oldest participants around age 50 years. In nearly all age groups the largest part of the variation in head circumference was explained by genetic differences. Heritability estimates were 90% in young infants (4 to 5 months), 85–88% in early childhood, 83–87% in adolescence, 75% in young and mid adulthood. In infants younger than 3 months, heritability was very low or absent. Quantitative sex differences in heritability were observed in 15- and 18-year-olds, but there was no evidence for qualitative sex differences, that is, the same genes were expressed in both males and females. Longitudinal analysis of the data between 5, 7, and 18 years of age showed high genetic stability (.78 > RG> .98). These results indicate that head circumference is a highly heritable biometric trait and a valid target for future GWA studies.

AbstractAmultidisciplinary collaborative study examining cognition in a large sample of twins is outlined. A common experimental protocol and design is used in The Netherlands, Australia and Japan to measure cognitive ability using traditional IQ measures (i.e., psychometric IQ), processing speed (e.g., reaction time [RT] and inspection time [IT]), and working memory (e.g., spatial span, delayed response [DR] performance). The main aim is to investigate the genetic covariation among these cognitive phenotypes in order to use the correlated biological markers in future linkage and association analyses to detect quantitativetrait loci (QTLs). We outline the study and methodology, and report results from our preliminary analyses that examines the heritability of processing speed and working memory indices, and their phenotypic correlation with IQ. Heritability of Full Scale IQ was 87% in the Netherlands, 83% in Australia, and 71% in Japan. Heritability estimates for processing speed and working memory indices ranged from 33–64%. Associations of IQ with RT and IT (−0.28 to −0.36) replicated previous findings with those of higher cognitive ability showing faster speed of processing. Similarly, significant correlations were indicated between IQ and the spatial span working memory task (storage [0.31], executive processing [0.37]) and the DR working memory task (0.25), with those of higher cognitive ability showing better memory performance. These analyses establish the heritability of the processing speed and working memory measures to be used in our collaborative twin study of cognition, and support the findings that individual differences in processing speed and working memory may underlie individual differences in psychometric IQ.

Variation in human cognitive ability is of consequence to a large number of health and social outcomes and is substantially heritable. Genetic linkage, genome-wide association, and copy number variant studies have investigated the contribution of genetic variation to individual differences in normal cognitive ability, but little research has considered the role of rare genetic variants. Exome sequencing studies have already met with success in discovering novel trait-gene associations for other complex traits. Here, we use exome sequencing to investigate the effects of rare variants on general cognitive ability. Unrelated Scottish individuals were selected for high scores on a general component of intelligence (g). The frequency of rare genetic variants (in n = 146) was compared with those from Scottish controls (total n = 486) who scored in the lower to middle range of the g distribution or on a proxy measure of g. Biological pathway analysis highlighted enrichment of the mitochondrial inner membrane component and apical part of cell gene ontology terms. Global burden analysis showed a greater total number of rare variants carried by high g cases versus controls, which is inconsistent with a mutation load hypothesis whereby mutations negatively affect g. The general finding of greater non-synonymous (vs. synonymous) variant effects is in line with evolutionary hypotheses for g. Given that this first sequencing study of high g was small, promising results were found, suggesting that the study of rare variants in larger samples would be worthwhile.

Generation Scotland has received core funding from the Chief Scientist Office of the Scottish Government Health DirectoratesCZD/16/6 and the Scottish Funding CouncilHR03006. We are grateful to all the families who took part, the general practitioners and the Scottish School of Primary Care for their help in recruiting them, and the whole Generation Scotland team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, healthcare assistants and nurses. Genotyping of the GS:SFHS samples was carried out by the Genetics Core Laboratory at the Wellcome Trust Clinical Research Facility, Edinburgh, Scotland and was funded by the UK's Medical Research Council. The Quantitative Trait Locus team at the Human Genetics Unit is funded by the Medical Research Council. REM, GD, DL, ML, DJP, PMV, and IJD undertook the work within The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology (MR/K026992/1), part of the cross council Lifelong Health and Wellbeing Initiative. Funding from the BBSRC and MRC is gratefully acknowledged. REM is an Alzheimer's Research UK Fellow (ART-RF2010-2). ; Peer reviewed ; Publisher PDF