Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region With Cortical and Subcortical Morphology and Cognition

Importance: Recurrent microdeletions and duplications in the genomic region 15q11.2 between breakpoints 1 (BP1) and 2 (BP2) are associated with neurodevelopmental disorders. These structural variants are present in 0.5% to 1.0% of the population, making 15q11.2 BP1-BP2 the site of the most prevalent known pathogenic copy number variation (CNV). It is unknown to what extent this CNV influences brain structure and affects cognitive abilities. Objective: To determine the association of the 15q11.2 BP1-BP2 deletion and duplication CNVs with cortical and subcortical brain morphology and cognitive task performance. Design, Setting, and Participants: In this genetic association study, T1-weighted brain magnetic resonance imaging were combined with genetic data from the ENIGMA-CNV consortium and the UK Biobank, with a replication cohort from Iceland. In total, 203 deletion carriers, 45 247 noncarriers, and 306 duplication carriers were included. Data were collected from August 2015 to April 2019, and data were analyzed from September 2018 to September 2019. Main Outcomes and Measures: The associations of the CNV with global and regional measures of surface area and cortical thickness as well as subcortical volumes were investigated, correcting for age, age2, sex, scanner, and intracranial volume. Additionally, measures of cognitive ability were analyzed in the full UK Biobank cohort. Results: Of 45 756 included individuals, the mean (SD) age was 55.8 (18.3) years, and 23 754 (51.9%) were female. Compared with noncarriers, deletion carriers had a lower surface area (Cohen d = -0.41; SE, 0.08; P = 4.9 × 10-8), thicker cortex (Cohen d = 0.36; SE, 0.07; P = 1.3 × 10-7), and a smaller nucleus accumbens (Cohen d = -0.27; SE, 0.07; P = 7.3 × 10-5). There was also a significant negative dose response on cortical thickness (β = -0.24; SE, 0.05; P = 6.8 × 10-7). Regional cortical analyses showed a localization of the effects to the frontal, cingulate, and parietal lobes. Further, cognitive ability was lower for deletion carriers compared with noncarriers on 5 of 7 tasks. Conclusions and Relevance: These findings, from the largest CNV neuroimaging study to date, provide evidence that 15q11.2 BP1-BP2 structural variation is associated with brain morphology and cognition, with deletion carriers being particularly affected. The pattern of results fits with known molecular functions of genes in the 15q11.2 BP1-BP2 region and suggests involvement of these genes in neuronal plasticity. These neurobiological effects likely contribute to the association of this CNV with neurodevelopmental disorders

Population-specific genotype imputations using minimac or IMPUTE2

In order to meaningfully analyze common and rare genetic variants, results from genome-wide association studies (GWASs) of multiple cohorts need to be combined in a meta-analysis in order to obtain enough power. This requires all cohorts to have the same single-nucleotide polymorphisms (SNPs) in their GWASs. To this end, genotypes that have not been measured in a given cohort can be imputed on the basis of a set of reference haplotypes. This protocol provides guidelines for performing imputations

A characterization of cis- and trans-heritability of RNA-Seq-based gene expression

Insights into individual differences in gene expression and its heritability (h2) can help in understanding pathways from DNA to phenotype. We estimated the heritability of gene expression of 52,844 genes measured in whole blood in the largest twin RNA-Seq sample to date (1497 individuals including 459 monozygotic twin pairs and 150 dizygotic twin pairs) from classical twin modeling and identity-by-state-based approaches. We estimated for each gene h2 total, composed of cis-heritability (h2 cis, the variance explained by single nucleotide polymorphisms in the cis-window of the gene), and trans-heritability (h2 res, the residual variance explained by all other genome-wide variants). Mean h2 total was 0.26, which was significantly higher than heritability estimates earlier found in a microarray-based study using largely overlapping (>60%) RNA samples (mean h2 = 0.14, p = 6.15 × 10−258). Mean h2 cis was 0.06 and strongly correlated with beta of the top cis expression quantitative loci (eQTL, ρ = 0.76, p < 10−308) and with estimates from earlier RNA-Seq-based studies. Mean h2 res was 0.20 and correlated with the beta of the corresponding trans-eQTL (ρ = 0.04, p < 1.89 × 10−3) and was significantly higher for genes involved in cytokine-cytokine interactions (p = 4.22 × 10−15), many other immune system pathways, and genes identified in genome-wide association studies for various traits including behavioral disorders and cancer. This study provides a thorough characterization of cis- and trans-h2 estimates of gene expression, which is of value for interpretation of GWAS and gene expression studies

Associations between smoking and caffeine consumption in two European cohorts

AIMS: To estimate associations between smoking initiation, smoking persistence and smoking heaviness and caffeine consumption in two population‐based samples from the Netherlands and the United Kingdom. DESIGN: Observational study employing data on self‐reported smoking behaviour and caffeine consumption. SETTING: Adults from the general population in the Netherlands and the United Kingdom. PARTICIPANTS: Participants from the Netherlands Twin Register [NTR: n = 21 939, mean age 40.8, standard deviation (SD) = 16.9, 62.6% female] and the Avon Longitudinal Study of Parents and Children (ALSPAC: n = 9086, mean age 33.2, SD = 4.7, 100% female). MEASUREMENTS: Smoking initiation (ever versus never smoking), smoking persistence (current versus former smoking), smoking heaviness (number of cigarettes smoked) and caffeine consumption in mg per day through coffee, tea, cola and energy drinks. FINDINGS: After correction for age, gender (NTR), education and social class (ALSPAC), smoking initiation was associated with consuming on average 52.8 [95% confidence interval (CI) = 45.6–60.0; NTR] and 59.5 (95% CI = 51.8–67.2; ALSPAC) mg more caffeine per day. Smoking persistence was also associated with consuming more caffeine [+57.9 (95% CI = 45.2–70.5) and +83.2 (95% CI = 70.2–96.3) mg, respectively]. Each additional cigarette smoked per day was associated with 3.7 (95% CI = 1.9–5.5; NTR) and 8.4 (95% CI = 6.9–10.0; ALSPAC) mg higher daily caffeine consumption in current smokers. Smoking was associated positively with coffee consumption and less strongly with cola and energy drinks. For tea, associations were positive in ALSPAC and negative in NTR. CONCLUSIONS: There appears to be a positive association between smoking and caffeine consumption in the Netherlands and the United Kingdom

Heritability and genome-wide linkage scan of subjective happiness

Causes of individual differences in happiness, as assessed with the Subjective Happiness Scale, are investigated in a large of sample twins and siblings from the Netherlands Twin Register. Over 12,000 twins and siblings, average age 24.7 years (range 12 to 88), took part in the study. A genetic model with an age by sex design was fitted to the data with structural equation modeling in Mx. The heritability of happiness was estimated at 22% for males and 41% in females. No effect of age was observed. To identify the genomic regions contributing to this heritability, a genome-wide linkage study for happiness was conducted in sibling pairs. A subsample of 1157 offspring from 441 families was genotyped with an average of 371 micro-satellite markers per individual. Phenotype and genotype data were analyzed in MERLIN with multipoint variance component linkage analysis and age and sex as covariates. A linkage signal (logarithm of odds score 2.73, empirical p value 0.095) was obtained at the end of the long arm of chromosome 19 for marker D19S254 at 110 cM. A second suggestive linkage peak was found at the short arm of chromosome 1 (LOD of 2.37) at 153 cM, marker D1S534 (empirical p value of .209). These two regions of interest are not overlapping with the regions found for contrasting phenotypes (such as depression, which is negatively associated with happiness). Further linkage and future association studies are warranted