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1.  Genome Wide Linkage Analysis of Multiple Measures of Neuroticism of two large cohorts from Australia and the Netherlands 
Archives of general psychiatry  2008;65(6):649-658.
Context
People meeting diagnostic criteria for anxiety or depressive disorders tend to score high on the personality scale of neuroticism. Studying this personality dimension can give insights into the aetiology of these important psychiatric disorders.
Objective
To undertake a comprehensive genome-wide linkage study of neuroticism, using large study samples that have been measured multiple times. To compare the results between countries for replication and across time within countries for consistency.
Design
Genome wide linkage scan.
Setting
Twin individuals and their family members from Australia (AU) and the Netherlands (NL).
Participants
19,635 sibling pairs completed self-report questionnaires for neuroticism up to five times over a period of up to 22 years. 5,069 sibling pairs were genotyped with microsatellite markers.
Methods
Non-parametric linkage analyses were conducted in Merlin-Regress for the mean neuroticism scores averaged across time. Additional analyses were conducted for the time specific measures of neuroticism from each country to investigate consistency of linkage results.
Results
Three chromosomal regions exceeded empirically-derived thresholds for suggestive linkage using mean neuroticism scores: 10p 5 cM (NL), 14q 103 cM (NL) and 18q 117 cM (AU & NL combined), but only 14q retains significance after correction for multiple testing. These regions all showed evidence for linkage in individual time-specific measures of neuroticism and one (18q) showed some evidence for replication between countries. Linkage intervals for these regions all overlap with regions identified in other studies of neuroticism or related traits and/or in studies of anxiety in mice.
Conclusions
Our results demonstrate the value of the availability of multiple measures over time and add to the optimism reported in recent reviews for replication of linkage regions for neuroticism. These regions are likely to harbour causal variants for neuroticism and its related psychiatric disorders and can inform prioritisation of results from genome-wide association studies.
doi:10.1001/archpsyc.65.6.649
PMCID: PMC3912824  PMID: 18519823
2.  Sex differences in the human peripheral blood transcriptome 
BMC Genomics  2014;15:33.
Background
Genomes of men and women differ in only a limited number of genes located on the sex chromosomes, whereas the transcriptome is far more sex-specific. Identification of sex-biased gene expression will contribute to understanding the molecular basis of sex-differences in complex traits and common diseases.
Results
Sex differences in the human peripheral blood transcriptome were characterized using microarrays in 5,241 subjects, accounting for menopause status and hormonal contraceptive use. Sex-specific expression was observed for 582 autosomal genes, of which 57.7% was upregulated in women (female-biased genes). Female-biased genes were enriched for several immune system GO categories, genes linked to rheumatoid arthritis (16%) and genes regulated by estrogen (18%). Male-biased genes were enriched for genes linked to renal cancer (9%). Sex-differences in gene expression were smaller in postmenopausal women, larger in women using hormonal contraceptives and not caused by sex-specific eQTLs, confirming the role of estrogen in regulating sex-biased genes.
Conclusions
This study indicates that sex-bias in gene expression is extensive and may underlie sex-differences in the prevalence of common diseases.
doi:10.1186/1471-2164-15-33
PMCID: PMC3904696  PMID: 24438232
4.  Estimating the genetic variance of Major Depressive Disorder (MDD) due to all SNPs 
Biological psychiatry  2012;72(8):707-709.
Genome-wide association (GWA) studies of psychiatric disorders have been criticized for their lack in explaining a considerable proportion of the heritability established in twin and family studies. GWA studies of Major Depressive Disorder (MDD) in particular have so far been unsuccessful in detecting genome-wide significant SNPs. Using two different recently proposed methods designed to estimate the heritability of a phenotype that is attributable to genome-wide SNPs, we show that SNPs on current platforms contain substantial information concerning the additive genetic variance of MDD. To assess the consistency of these two different methods we analyzed four other complex phenotypes from different domains. The pattern of results is consistent with estimates of heritability obtained in twin studies carried out in the same population.
doi:10.1016/j.biopsych.2012.03.011
PMCID: PMC3404250  PMID: 22520966
5.  Genome-wide association uncovers shared genetic effects among personality traits and mood states 
Measures of personality and psychological distress are correlated and exhibit genetic covariance. We conducted univariate genome-wide SNP (~2.5 million) and gene-based association analyses of these traits and examined the overlap in results across traits, including a prediction analysis of mood states using genetic polygenic scores for personality. Measures of neuroticism, extraversion, and symptoms of anxiety, depression, and general psychological distress were collected in eight European cohorts (n ranged 546 to 1 338; maximum total n=6 268) whose mean age ranged from 55 to 79 years. Meta-analysis of the cohort results was performed, with follow-up associations of the top SNPs and genes investigated in independent cohorts (n=527 to 6 032). Suggestive association (P=8×10−8) of rs1079196 in the FHIT gene was observed with symptoms of anxiety. Other notable associations (P<6.09×10−6) included SNPs in five genes for neuroticism (LCE3C, POLR3A, LMAN1L, ULK3, SCAMP2), KIAA0802 for extraversion, and NOS1 for general psychological distress. An association between symptoms of depression and rs7582472 (near to MGAT5 and NCKAP5) was replicated in two independent samples, but other replication findings were less consistent. Gene-based tests identified a significant locus on chromosome 15 (spanning five genes) associated with neuroticism which replicated (P<0.05) in an independent cohort. Support for common genetic effects among personality and mood (particularly neuroticism and depressive symptoms) was found in terms of SNP association overlap and polygenic score prediction. The variance explained by individual SNPs was very small (up to 1%) confirming that there are no moderate/large effects of common SNPs on personality and related traits.
doi:10.1002/ajmg.b.32072
PMCID: PMC3795298  PMID: 22628180
GWAS; extraversion; neuroticism; anxiety; depression
6.  Meta-analyses of genome-wide linkage scans of anxiety-related phenotypes 
European Journal of Human Genetics  2012;20(10):1078-1084.
Genetic factors underlying trait neuroticism, reflecting a tendency towards negative affective states, may overlap genetic susceptibility for anxiety disorders and help explain the extensive comorbidity amongst internalizing disorders. Genome-wide linkage (GWL) data from several studies of neuroticism and anxiety disorders have been published, providing an opportunity to test such hypotheses and identify genomic regions that harbor genes common to these phenotypes. In all, 11 independent GWL studies of either neuroticism (n=8) or anxiety disorders (n=3) were collected, which comprised of 5341 families with 15 529 individuals. The rank-based genome scan meta-analysis (GSMA) approach was used to analyze each trait separately and combined, and global correlations between results were examined. False discovery rate (FDR) analysis was performed to test for enrichment of significant effects. Using 10 cM intervals, bins nominally significant for both GSMA statistics, PSR and POR, were found on chromosomes 9, 11, 12, and 14 for neuroticism and on chromosomes 1, 5, 15, and 16 for anxiety disorders. Genome-wide, the results for the two phenotypes were significantly correlated, and a combined analysis identified additional nominally significant bins. Although none reached genome-wide significance, an excess of significant PSRP-values were observed, with 12 bins falling under a FDR threshold of 0.50. As demonstrated by our identification of multiple, consistent signals across the genome, meta-analytically combining existing GWL data is a valuable approach to narrowing down regions relevant for anxiety-related phenotypes. This may prove useful for prioritizing emerging genome-wide association data for anxiety disorders.
doi:10.1038/ejhg.2012.47
PMCID: PMC3449070  PMID: 22473089
anxiety; neuroticism; panic disorder; linkage; meta-analysis
7.  Meta-analysis of genome-wide association studies for personality 
Molecular psychiatry  2010;17(3):337-349.
Personality can be thought of as a set of characteristics that influence people’s thoughts, feelings, and behaviour across a variety of settings. Variation in personality is predictive of many outcomes in life, including mental health. Here we report on a meta-analysis of genome-wide association (GWA) data for personality in ten discovery samples (17 375 adults) and five in-silico replication samples (3 294 adults). All participants were of European ancestry. Personality scores for Neuroticism, Extraversion, Openness to Experience, Agreeableness, and Conscientiousness were based on the NEO Five-Factor Inventory. Genotype data were available of ~2.4M Single Nucleotide Polymorphisms (SNPs; directly typed and imputed using HAPMAP data). In the discovery samples, classical association analyses were performed under an additive model followed by meta-analysis using the weighted inverse variance method. Results showed genome-wide significance for Openness to Experience near the RASA1 gene on 5q14.3 (rs1477268 and rs2032794, P = 2.8 × 10−8 and 3.1 × 10−8) and for Conscientiousness in the brain-expressed KATNAL2 gene on 18q21.1 (rs2576037, P = 4.9 × 10−8). We further conducted a gene-based test that confirmed the association of KATNAL2 to Conscientiousness. In-silico replication did not, however, show significant associations of the top SNPs with Openness and Conscientiousness, although the direction of effect of the KATNAL2 SNP on Conscientiousness was consistent in all replication samples. Larger scale GWA studies and alternative approaches are required for confirmation of KATNAL2 as a novel gene affecting Conscientiousness.
doi:10.1038/mp.2010.128
PMCID: PMC3785122  PMID: 21173776
Personality; Five-Factor Model; Genome-wide association; Meta-analysis; Genetic variants
9.  BORDERLINE PERSONALITY TRAITS AND SUBSTANCE USE: GENETIC FACTORS UNDERLIE THE ASSOCIATION WITH SMOKING AND EVER USE OF CANNABIS, BUT NOT WITH HIGH ALCOHOL CONSUMPTION 
Journal of personality disorders  2012;26(6):867-879.
Borderline personality disorder (BPD) and substance use disorders often co-occur. Both disorders are heritable and family studies showed that there are familial factors that increase the risk for BPD as well as substance use/abuse. This is the first study that investigates whether the association of borderline personality traits (BPT) with substance use reflects an underlying genetic vulnerability or nongenetic familial influences. To this end we analyzed data of 5,638 Dutch and Belgian twins aged between 21–50 years from 3,567 families. Significant associations between BPT and high alcohol consumption (r = .192), regular smoking (r = .299), and ever use of cannabis (r = .254) were found. Bivariate genetic analyses showed that the associations of BPT and substance use had different etiologies. For regular smoking and for ever use of cannabis, the correlation with BPT was explained by common genetic factors. Interestingly, for high alcohol consumption and BPT the association was explained by unique environmental factors that influence both traits rather than common genetic factors.
doi:10.1521/pedi.2012.26.6.867
PMCID: PMC3744119  PMID: 23281672
10.  The Adult Netherlands Twin Register: Twenty-Five Years of Survey and Biological Data Collection 
Over the past 25 years, the Adult Netherlands Twin Register (ANTR) has collected a wealth of information on physical and mental health, lifestyle, and personality in adolescents and adults. This article provides an overview of the sources of information available, the main research findings, and an outlook for the future. Between 1991 and 2012, longitudinal surveys were completed by twins, their parents, siblings, spouses, and offspring. Data are available for 33,957 participants, with most individuals having completed two or more surveys. Smaller projects provided in-depth phenotyping, including measurements of the autonomic nervous system, neurocognitive function, and brain imaging. For 46% of the ANTR participants, DNA samples are available and whole genome scans have been obtained in more than 11,000 individuals. These data have resulted in numerous studies on heritability, gene × environment interactions, and causality, as well as gene finding studies. In the future, these studies will continue with collection of additional phenotypes, such as metabolomic and telomere length data, and detailed genetic information provided by DNA and RNA sequencing. Record linkage to national registers will allow the study of morbidity and mortality, thus providing insight into the development of health, lifestyle, and behavior across the lifespan.
doi:10.1017/thg.2012.140
PMCID: PMC3739974  PMID: 23298648
twin family studies; gene finding; longitudinal surveys; biobank; DNA
11.  Epigenetic variation during the adult lifespan: cross-sectional and longitudinal data on monozygotic twin pairs 
Aging Cell  2012;11(4):694-703.
The accumulation of epigenetic changes was proposed to contribute to the age-related increase in the risk for most common diseases. In this study on 230 monozygotic twin pairs (MZ pairs), aged 18 to 89 years old, we investigated the occurrence of epigenetic changes over the adult lifespan. Using mass spectrometry, we investigated variation in global (LINE1) DNA methylation and in DNA methylation at INS, KCNQ1OT1, IGF2, GNASAS, ABCA1, LEP, and CRH, candidate loci for common diseases. Except for KCNQ1OT1, inter-individual variation in locus specific DNA methylation was larger in old individuals than in young individuals, ranging from 1.2 fold larger at ABCA1 (p = 0.010) to 1.6 fold larger at INS (p = 3.7 * 10−07). Similarly, there was more within-MZ-pair discordance in old as compared with young MZ pairs, except for GNASAS, ranging from an 8 % increase in discordance each decade at CRH (p = 8.9 * 10−06) to a 16 % increase each decade at LEP (p = 2.0 * 10−08). Still, old MZ pairs with strikingly similar DNA methylation were also observed at these loci. After 10 year follow-up in elderly twins, the variation in DNA methylation showed a similar pattern of change as observed cross-sectionally. The age-related increase in methylation variation was generally due to unique environmental factors, except for CRH, for which familial factors may play a more important role. In conclusion, sustained epigenetic differences arise from early adulthood to old age and contribute to an increasing discordance of MZ twins during ageing.
doi:10.1111/j.1474-9726.2012.00835.x
PMCID: PMC3399918  PMID: 22621408
Epigenetics; Aging; MZ twin design; Full adult lifespan; DNA methylation; Stochastic variation
12.  GENETIC COVARIANCE STRUCTURE OF THE FOUR MAIN FEATURES OF BORDERLINE PERSONALITY DISORDER 
Journal of personality disorders  2010;24(4):427-444.
The patient population of borderline personality disorder (BPD) is heterogeneous; many different combinations of BPD symptoms can lead to a BPD diagnosis. We investigated to what extent the covariance among four main components of BPD is explained by shared genetic and environmental factors. Using an extended twin design, multivariate genetic models were applied to the scales of the PAI-BOR, a self-report questionnaire tapping four main features of BPD (affective instability, identity problems, negative relationships, and self-harm). Data on the four BPD scales were available for 5,533 twins and 1,202 siblings from the Netherlands, Belgium, and Australia. The correlations among the scales ranged from 0.23 to 0.50 and were best explained by a genetic common pathway model. This model specifies that genes and environment influence the covariance between four main features of BPD in qualitatively similar ways, through a single latent factor representing the BPD construct. The heritability of the latent BPD factor was 51% and the remainder of its variance was explained by unique environmental influences. For each BPD scale, except self-harm, around 50% of its variance was explained by the latent BPD factor. The remaining variance for each of the four scales was explained by genetic (4% for affective instability to 20% for self-harm) and environmental (38% for negative relationships to 67% for self-harm) factors that were specific to each scale.
doi:10.1521/pedi.2010.24.4.427
PMCID: PMC3705216  PMID: 20695804
13.  DeepSAGE Reveals Genetic Variants Associated with Alternative Polyadenylation and Expression of Coding and Non-coding Transcripts 
PLoS Genetics  2013;9(6):e1003594.
Many disease-associated variants affect gene expression levels (expression quantitative trait loci, eQTLs) and expression profiling using next generation sequencing (NGS) technology is a powerful way to detect these eQTLs. We analyzed 94 total blood samples from healthy volunteers with DeepSAGE to gain specific insight into how genetic variants affect the expression of genes and lengths of 3′-untranslated regions (3′-UTRs). We detected previously unknown cis-eQTL effects for GWAS hits in disease- and physiology-associated traits. Apart from cis-eQTLs that are typically easily identifiable using microarrays or RNA-sequencing, DeepSAGE also revealed many cis-eQTLs for antisense and other non-coding transcripts, often in genomic regions containing retrotransposon-derived elements. We also identified and confirmed SNPs that affect the usage of alternative polyadenylation sites, thereby potentially influencing the stability of messenger RNAs (mRNA). We then combined the power of RNA-sequencing with DeepSAGE by performing a meta-analysis of three datasets, leading to the identification of many more cis-eQTLs. Our results indicate that DeepSAGE data is useful for eQTL mapping of known and unknown transcripts, and for identifying SNPs that affect alternative polyadenylation. Because of the inherent differences between DeepSAGE and RNA-sequencing, our complementary, integrative approach leads to greater insight into the molecular consequences of many disease-associated variants.
Author Summary
Many genetic variants that are associated with diseases also affect gene expression levels. We used a next generation sequencing approach targeting 3′ transcript ends (DeepSAGE) to gain specific insight into how genetic variants affect the expression of genes and the usage and length of 3′-untranslated regions. We detected many associations for antisense and other non-coding transcripts, often in genomic regions containing retrotransposon-derived elements. Some of these variants are also associated with disease. We also identified and confirmed variants that affect the usage of alternative polyadenylation sites, thereby potentially influencing the stability of mRNAs. We conclude that DeepSAGE is useful for detecting eQTL effects on both known and unknown transcripts, and for identifying variants that affect alternative polyadenylation.
doi:10.1371/journal.pgen.1003594
PMCID: PMC3688553  PMID: 23818875
14.  Increases in alcohol consumption in women and elderly groups: evidence from an epidemiological study 
BMC Public Health  2013;13:207.
Background
In most Western countries, alcohol consumption continues to increase, specifically among women and older adults. Insight into these trends may aid intervention strategies. Here we present data on alcohol consumption by age and sex as well as associations between alcohol use and demographic lifestyle/traits. The data are from a large (N>16,000) population-based Dutch sample, ascertained based on the presence of twins in the family.
Methods
A set of 16 indicators of normative and problematic alcohol use was assessed in participants of the Netherlands Twin Register between 2009–2012 (ages 18–97; 6,052 men; 10,535 women). Alcohol consumption and demographic/lifestyle traits, including educational attainment, work-related/financial stress, urbanization, religiousness, smoking/cannabis initiation, and BMI were described by age and sex. Associations were examined by regressing aspects of alcohol use on age, sex, their interaction, and demographic/lifestyle variables.
Results
Age, sex, and initiation of cigarette and cannabis use were the most important predictors of alcohol use. Frequency of alcohol use was lowest between 18–25 years, with 3.2% of men and .6% of women drinking 6–7 times/week, and highest above age 65 years, with 30.6-32.7% of men and 20.2-22.0% of women drinking 6–7 times/week. Women consumed the lowest quantities of alcohol between 25–45 years, with a 5.7-5.9% prevalence of excessive drinking (>14 glasses/week), and the largest quantities between 55–65 years (15.5% excessive drinkers). Age at alcohol initiation, onset of regular drinking, and first alcohol intoxication were lowest between ages 18–25 years and highest above age 65 years. Among older participants, men initiated alcohol use and regular drinking earlier, and had lower age at first intoxication than women, but among young adults, no sex differences were observed.
Conclusions
Alcohol consumption was high in the elderly Dutch population, especially among women. Alcohol initiation, onset of regular drinking, and first alcohol intoxication occur at increasingly younger ages, and the previous gap between men and women in age at alcohol initiation, onset of regular drinking, and first alcohol intoxication has closed almost entirely. Heavy alcohol use was most strongly predicted by older age, sex (male), and initiation of smoking and cannabis use.
doi:10.1186/1471-2458-13-207
PMCID: PMC3720280  PMID: 23497391
Alcohol consumption; Young adults; Women; Older adults; Epidemiology; Demographic variables; Lifestyle variables
15.  Loci affecting gamma-glutamyl transferase in adults and adolescents show age × SNP interaction and cardiometabolic disease associations 
Human Molecular Genetics  2011;21(2):446-455.
Serum gamma-glutamyl transferase (GGT) activity is a marker of liver disease which is also prospectively associated with the risk of all-cause mortality, cardiovascular disease, type 2 diabetes and cancers. We have discovered novel loci affecting GGT in a genome-wide association study (rs1497406 in an intergenic region of chromosome 1, P = 3.9 × 10−8; rs944002 in C14orf73 on chromosome 14, P = 4.7 × 10−13; rs340005 in RORA on chromosome 15, P = 2.4 × 10−8), and a highly significant heterogeneity between adult and adolescent results at the GGT1 locus on chromosome 22 (maximum PHET = 5.6 × 10−12 at rs6519520). Pathway analysis of significant and suggestive single-nucleotide polymorphism associations showed significant overlap between genes affecting GGT and those affecting common metabolic and inflammatory diseases, and identified the hepatic nuclear factor (HNF) family as controllers of a network of genes affecting GGT. Our results reinforce the disease associations of GGT and demonstrate that control by the GGT1 locus varies with age.
doi:10.1093/hmg/ddr478
PMCID: PMC3276286  PMID: 22010049
16.  Genetic and Environmental Contributions Self-Reported Thoughts of Self-Harm and Suicide 
American Journal of Medical Genetics  2011;159B(1):120-127.
Thoughts of self-harm and suicidal behavior are thought to be influenced by both genetics and environment. Molecular genetic studies are beginning to address the question of which genes may be involved and whether different genes may be expressed in men and women. We examined thoughts of self-harm and suicidal behavior in a large general population twin sample including male and female same- and opposite-sex twins. In this study, data on self-reported thoughts of self-harm and suicide were obtained from self-report questionnaires (Beck Depression Inventory and Youth or Adult Self Report forms) in 6265 twin pairs (11,008 individuals) aged 11–90 (62% female) from the Netherlands Twin Registry. Liability threshold models were compared including sex and age (linear and quadratic) effects. Models were compared using measures of parsimony to calculate the simplest model to the data. A model with additive genetic and unique environmental contributions fitted the data for both males and females. There were no qualitative sex differences, but the relative contributions differed between men and women. Heritability was higher in women (0.74, 95% CI 0.65 – 0.81) than men (0.45, 95% CI 0.28 – 0.61). The remaining variance was accounted for by environmental influence unique to an individual. These results suggest contributions from additive genetic factors to self-reported thoughts of self-harm and suicide and support the continued study of both molecular genetic and individual-specific environmental risk factors.
doi:10.1002/ajmg.b.32010
PMCID: PMC3254180  PMID: 22162437
Suicide; Twins; Behavioral Genetics
17.  Sex Differences in Genetic Architecture of Complex Phenotypes? 
PLoS ONE  2012;7(12):e47371.
We examined sex differences in familial resemblance for a broad range of behavioral, psychiatric and health related phenotypes (122 complex traits) in children and adults. There is a renewed interest in the importance of genotype by sex interaction in, for example, genome-wide association (GWA) studies of complex phenotypes. If different genes play a role across sex, GWA studies should consider the effect of genetic variants separately in men and women, which affects statistical power. Twin and family studies offer an opportunity to compare resemblance between opposite-sex family members to the resemblance between same-sex relatives, thereby presenting a test of quantitative and qualitative sex differences in the genetic architecture of complex traits. We analyzed data on lifestyle, personality, psychiatric disorder, health, growth, development and metabolic traits in dizygotic (DZ) same-sex and opposite-sex twins, as these siblings are perfectly matched for age and prenatal exposures. Sample size varied from slightly over 300 subjects for measures of brain function such as EEG power to over 30,000 subjects for childhood psychopathology and birth weight. For most phenotypes, sample sizes were large, with an average sample size of 9027 individuals. By testing whether the resemblance in DZ opposite-sex pairs is the same as in DZ same-sex pairs, we obtain evidence for genetic qualitative sex-differences in the genetic architecture of complex traits for 4% of phenotypes. We conclude that for most traits that were examined, the current evidence is that same the genes are operating in men and women.
doi:10.1371/journal.pone.0047371
PMCID: PMC3525575  PMID: 23272036
18.  Identification of IL6R and chromosome 11q13.5 as risk loci for asthma 
Lancet  2011;378(9795):1006-1014.
Background
We aimed to identify novel genetic variants affecting asthma risk, since these might provide novel insights into molecular mechanisms underlying asthma.
Methods
We performed a genome-wide association study (GWAS) in 2,669 physician-diagnosed asthmatics and 4,528 controls from Australia. Seven loci were prioritised for replication after combining our results with those from the GABRIEL consortium (n=26,475), and these were tested in an additional 25,358 independent samples from four in-silico cohorts. Quantitative multi-SNP scores of genetic load were constructed on the basis of results from the GABRIEL study and tested for association with asthma in our Australian GWAS dataset.
Findings
Two loci were confirmed to associate with asthma risk in the replication cohorts and reached genome-wide significance in the combined analysis of all available studies (n=57,800): rs4129267 (OR=1.09, combined P=2.4×10−8) in the interleukin-6 receptor gene (IL6R) and rs7130588 (OR=1.09, P=1.8×10−8) on chromosome 11q13.5 near the leucine-rich repeat containing 32 gene (LRRC32, also known as GARP). The 11q13.5 locus was significantly associated with atopic status among asthmatics (OR = 1.33, P = 7×10−4), suggesting that it is a risk factor for allergic but not non-allergic asthma. Multi-SNP association results are consistent with a highly polygenic contribution to asthma risk, including loci with weak effects that may be shared with other immune-related diseases, such as NDFIP1, HLA-B, LPP and BACH2.
Interpretation
The IL6R association further supports the hypothesis that cytokine signalling dysregulation affects asthma risk, and raises the possibility that an IL6R antagonist (tocilizumab) may be effective to treat the disease, perhaps in a genotype-dependent manner. Results for the 11q13.5 locus suggest that it directly increases the risk of allergic sensitisation which, in turn, increases the risk of subsequent development of asthma. Larger or more functionally focused studies are needed to characterise the many loci with modest effects that remain to be identified for asthma.
Funding
A full list of funding sources appears at the end of the paper.
doi:10.1016/S0140-6736(11)60874-X
PMCID: PMC3517659  PMID: 21907864
19.  Adolescent Personality Profiles, Neighborhood Income, and Young Adult Alcohol Use: A Longitudinal Study 
Addictive behaviors  2011;36(12):1301-1304.
Personality traits and socioeconomic factors such as neighborhood income have been identified as risk factors for future alcohol abuse, but findings have been inconsistent possibly due to interactions between risk and protective factors. The present study examined the prediction of drinking behavior using empirically derived multi-trait patterns and tested for moderation by average neighborhood income. Using latent profile analysis (LPA) in a sample of 863 Dutch adolescents, four empirical personality profiles based on 6 traits were observed: Extraverted, Dysregulated, Neurotic, and Regulated. Dysregulated and Extraverted youth drank higher quantities of alcohol more frequently in young adulthood relative to the Regulated group, above and beyond the effects of baseline adolescent drinking, age, and sex. Profile levels of neuroticism did not appear to affect drinking behavior. Average neighborhood income did not moderate adolescent personality and young adult drinking. These findings suggest that future alcohol research should consider individual trait patterns to inform prevention and intervention efforts, and theories implicating both positive and negative emotionality traits as risk factors for drinking are preferable to those emphasizing the importance of the latter.
doi:10.1016/j.addbeh.2011.07.004
PMCID: PMC3179794  PMID: 21820248
Personality; Neighborhood Income; Socioeconomic Status; Alcohol; Drinking
20.  A 3p26-3p25 genetic linkage finding for DSM-IV major depression in heavy smoking families 
The American journal of psychiatry  2011;168(8):848-852.
Objective
The authors tested for genetic linkage of DSM-IV-diagnosed major depressive disorder in families that were ascertained for cigarette smoking.
Method
Within a study that targeted families characterized by a history of smoking, analyses derived a subset of 91 Australian families with two or more offspring with a history of DSM-IV major depressive disorder (affected sibling pairs, N=187) and 25 Finnish families (affected sibling pairs, N=33). Within this affected sibling pair design, the authors conducted nonparametric linkage analysis.
Results
In the Australian heavy smoking families, the authors found a genome-wide significant multipoint LOD score of 4.14 for major depressive disorder on chromosome 3 at 24.9 cM (3p26-3p25).
Conclusions
Genome-wide significant linkage was detected for major depressive disorder on chromosome 3p in a sample ascertained for smoking. A linkage peak at this location was also observed in an independent study of major depressive disorder.
doi:10.1176/appi.ajp.2011.10091319
PMCID: PMC3433250  PMID: 21572167
21.  Genetic architecture of circulating lipid levels 
Serum concentrations of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TGs) and total cholesterol (TC) are important heritable risk factors for cardiovascular disease. Although genome-wide association studies (GWASs) of circulating lipid levels have identified numerous loci, a substantial portion of the heritability of these traits remains unexplained. Evidence of unexplained genetic variance can be detected by combining multiple independent markers into additive genetic risk scores. Such polygenic scores, constructed using results from the ENGAGE Consortium GWAS on serum lipids, were applied to predict lipid levels in an independent population-based study, the Rotterdam Study-II (RS-II). We additionally tested for evidence of a shared genetic basis for different lipid phenotypes. Finally, the polygenic score approach was used to identify an alternative genome-wide significance threshold before pathway analysis and those results were compared with those based on the classical genome-wide significance threshold. Our study provides evidence suggesting that many loci influencing circulating lipid levels remain undiscovered. Cross-prediction models suggested a small overlap between the polygenic backgrounds involved in determining LDL-C, HDL-C and TG levels. Pathway analysis utilizing the best polygenic score for TC uncovered extra information compared with using only genome-wide significant loci. These results suggest that the genetic architecture of circulating lipids involves a number of undiscovered variants with very small effects, and that increasing GWAS sample sizes will enable the identification of novel variants that regulate lipid levels.
doi:10.1038/ejhg.2011.21
PMCID: PMC3137496  PMID: 21448234
serum lipids; polygenic; genome-wide association; polygenic score; pathway analysis
23.  A Fine-Mapping Study of 7 Top Scoring Genes from a GWAS for Major Depressive Disorder 
PLoS ONE  2012;7(5):e37384.
Major depressive disorder (MDD) is a psychiatric disorder that is characterized -amongst others- by persistent depressed mood, loss of interest and pleasure and psychomotor retardation. Environmental circumstances have proven to influence the aetiology of the disease, but MDD also has an estimated 40% heritability, probably with a polygenic background. In 2009, a genome wide association study (GWAS) was performed on the Dutch GAIN-MDD cohort. A non-synonymous coding single nucleotide polymorphism (SNP) rs2522833 in the PCLO gene became only nominally significant after post-hoc analysis with an Australian cohort which used similar ascertainment. The absence of genome-wide significance may be caused by low SNP coverage of genes. To increase SNP coverage to 100% for common variants (m.a.f.>0.1, r2>0.8), we selected seven genes from the GAIN-MDD GWAS: PCLO, GZMK, ANPEP, AFAP1L1, ST3GAL6, FGF14 and PTK2B. We genotyped 349 SNPs and obtained the lowest P-value for rs2715147 in PCLO at P = 6.8E−7. We imputed, filling in missing genotypes, after which rs2715147 and rs2715148 showed the lowest P-value at P = 1.2E−6. When we created a haplotype of these SNPs together with the non-synonymous coding SNP rs2522833, the P-value decreased to P = 9.9E−7 but was not genome wide significant. Although our study did not identify a more strongly associated variant, the results for PCLO suggest that the causal variant is in high LD with rs2715147, rs2715148 and rs2522833.
doi:10.1371/journal.pone.0037384
PMCID: PMC3359349  PMID: 22649524
24.  Non-additive and Additive Genetic Effects on Extraversion in 3314 Dutch Adolescent Twins and Their Parents 
Behavior Genetics  2008;38(3):223-233.
The influence of non-additive genetic influences on personality traits has been increasingly reported in adult populations. Less is known, however, with respect to younger samples. In this study, we examine additive and non-additive genetic contributions to the personality trait of extraversion in 1,689 Dutch twin pairs, 1,505 mothers and 1,637 fathers of the twins. The twins were on average 15.5 years (range 12–18 years). To increase statistical power to detect non-additive genetic influences, data on extraversion were also collected in parents and simultaneously analyzed. Genetic modeling procedures incorporating age as a potential modifier of heritability showed significant influences of additive (20–23%) and non-additive genetic factors (31–33%) in addition to unshared environment (46–48%) for adolescents and for their parents. The additive genetic component was slightly and positively related to age. No significant sex differences were found for either extraversion means or for the magnitude of the genetic and environmental influences. There was no evidence of non-random mating for extraversion in the parental generation. Results show that in addition to additive genetic influences, extraversion in adolescents is influenced by non-additive genetic factors.
doi:10.1007/s10519-008-9192-5
PMCID: PMC3319035  PMID: 18240014
Personality; Temperament; Adolescence; Extraversion; Genetic; Environment
25.  The Genetic Architecture of Neuroticism in 3301 Dutch Adolescent Twins as a Function of Age and Sex: A Study From the Dutch Twin Register 
The objective of this study was to estimate the magnitude of genetic and environmental influences to variation in adolescent neuroticism as a function of age and sex. Neuroticism was assessed using the Amsterdamse Biografische Vragenlijst (ABV): a self-report personality instrument similar in content to the Eysenck Personality Questionnaire. Genetic modeling procedures, including age as modifier, were fitted to the total sample of 3301 Dutch adolescent twins aged 12 to 17 years (mean age 15.5). Significant influences of additive genetic factors (.59, 95% confidence intervals [CI] .54–.63) and unshared environmental factors (.41, 95% CI .37–.45) were found. Our data did not support a role of shared environment. Results showed that different genes may influence variation in neuroticism between girls and boys. No interaction was found between the variance components and age. Results generally support prior findings in adults and young children that neuroticism is influenced principally by additive genetic and unique environmental factors. The magnitude of the genetic component appears higher in the present sample of adolescents than in most studies of adults. The present study suggests that, in adolescence, different genes are expressed in boys and girls.
doi:10.1375/183242706776403028
PMCID: PMC3319038  PMID: 16611464

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