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1.  Re-sequencing Expands Our Understanding of the Phenotypic Impact of Variants at GWAS Loci 
PLoS Genetics  2014;10(1):e1004147.
Genome-wide association studies (GWAS) have identified >500 common variants associated with quantitative metabolic traits, but in aggregate such variants explain at most 20–30% of the heritable component of population variation in these traits. To further investigate the impact of genotypic variation on metabolic traits, we conducted re-sequencing studies in >6,000 members of a Finnish population cohort (The Northern Finland Birth Cohort of 1966 [NFBC]) and a type 2 diabetes case-control sample (The Finland-United States Investigation of NIDDM Genetics [FUSION] study). By sequencing the coding sequence and 5′ and 3′ untranslated regions of 78 genes at 17 GWAS loci associated with one or more of six metabolic traits (serum levels of fasting HDL-C, LDL-C, total cholesterol, triglycerides, plasma glucose, and insulin), and conducting both single-variant and gene-level association tests, we obtained a more complete understanding of phenotype-genotype associations at eight of these loci. At all eight of these loci, the identification of new associations provides significant evidence for multiple genetic signals to one or more phenotypes, and at two loci, in the genes ABCA1 and CETP, we found significant gene-level evidence of association to non-synonymous variants with MAF<1%. Additionally, two potentially deleterious variants that demonstrated significant associations (rs138726309, a missense variant in G6PC2, and rs28933094, a missense variant in LIPC) were considerably more common in these Finnish samples than in European reference populations, supporting our prior hypothesis that deleterious variants could attain high frequencies in this isolated population, likely due to the effects of population bottlenecks. Our results highlight the value of large, well-phenotyped samples for rare-variant association analysis, and the challenge of evaluating the phenotypic impact of such variants.
Author Summary
Abnormal serum levels of various metabolites, including measures relevant to cholesterol, other fats, and sugars, are known to be risk factors for cardiovascular disease and type 2 diabetes. Identification of the genes that play a role in generating such abnormalities could advance the development of new treatment and prevention strategies for these disorders. Investigations of common genetic variants carried out in large sets of research subjects have successfully pinpointed such genes within many regions of the human genome. However, these studies often have not led to the identification of the specific genetic variations affecting metabolic traits. To attempt to detect such causal variations, we sequenced genes in 17 genomic regions implicated in metabolic traits in >6,000 people from Finland. By conducting statistical analyses relating specific variations (individually and grouped by gene) to the measures for these metabolic traits observed in the study subjects, we added to our understanding of how genotypes affect these traits. Our findings support a long-held hypothesis that the unique history of the Finnish population provides important advantages for analyzing the relationship between genetic variations and biomedically important traits.
PMCID: PMC3907339  PMID: 24497850
2.  Genomic Variation in a Global Village: Report of the 10th Annual Human Genome Variation Meeting 2008 
Human mutation  2009;30(7):10.1002/humu.21008.
The Centre for Applied Genomics of the Hospital for Sick Children and the University of Toronto hosted the 10th Human Genome Variation (HGV) Meeting in Toronto, Canada, in October 2008, welcoming about 240 registrants from 34 countries. During the 3 days of plenary workshops, keynote address, and poster sessions, a strong cross-disciplinary trend was evident, integrating expertise from technology and computation, through biology and medicine, to ethics and law. Single nucleotide polymorphisms (SNPs) as well as the larger copy number variants (CNVs) are recognized by ever-improving array and next-generation sequencing technologies, and the data are being incorporated into studies that are increasingly genome-wide as well as global in scope. A greater challenge is to convert data to information, through databases, and to use the information for greater understanding of human variation. In the wake of publications of the first individual genome sequences, an inaugural public forum provided the opportunity to debate whether we are ready for personalized medicine through direct-to-consumer testing. The HGV meetings foster collaboration, and fruits of the interactions from 2008 are anticipated for the 11th annual meeting in September 2009.
PMCID: PMC3873344  PMID: 19384970
SNP; CNV; GWAS; personalized medicine
3.  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.
PMCID: PMC3785122  PMID: 21173776
Personality; Five-Factor Model; Genome-wide association; Meta-analysis; Genetic variants
4.  Genome-wide association study of intraocular pressure identifies the GLCCI1/ICA1 region as a glaucoma susceptibility locus 
Human Molecular Genetics  2013;22(22):4653-4660.
To discover quantitative trait loci for intraocular pressure, a major risk factor for glaucoma and the only modifiable one, we performed a genome-wide association study on a discovery cohort of 2175 individuals from Sydney, Australia. We found a novel association between intraocular pressure and a common variant at 7p21 near to GLCCI1 and ICA1. The findings in this region were confirmed through two UK replication cohorts totalling 4866 individuals (rs59072263, Pcombined = 1.10 × 10−8). A copy of the G allele at this SNP is associated with an increase in mean IOP of 0.45 mmHg (95%CI = 0.30–0.61 mmHg). These results lend support to the implication of vesicle trafficking and glucocorticoid inducibility pathways in the determination of intraocular pressure and in the pathogenesis of primary open-angle glaucoma.
PMCID: PMC3904806  PMID: 23836780
T-peak to T-end (TPE) interval on the electrocardiogram (ECG) is a measure of myocardial dispersion of repolarization and is associated with increased risk of ventricular arrhythmias. The genetic factors affecting the TPE interval are largely unknown.
We sought to identify common genetic variants that affect the TPE-interval duration in the general population.
We performed a genome-wide association study on 1 870 individuals of Finnish origin participating in the Health 2000 Study. TPE interval was measured from T-peak to T-wave end in leads II, V2 and V5 on resting ECGs and the mean of these TPE intervals was adjusted for age, sex and Cornell voltage-duration product. We sought replication for a genome-wide significant result in the 3 745 subjects from the Framingham Heart Study.
We identified a locus on 17q24 that was associated with the TPE interval. The minor allele of the common variant rs7219669 was associated with a 1.8-ms shortening of the TPE interval (P=1.1×10−10). The association was replicated in the Framingham Heart Study (−1.5 ms, P=1.3×10−4).The overall effect estimate of rs7219669 in the two studies was −1.7 ms (P=5.7×10−14). The common variant rs7219669 maps downstream of KCNJ2 gene, in which rare mutations cause congenital Long- and Short-QT syndromes.
The common variant rs7219669 is associated with the TPE interval and is thus a candidate to modify repolarization-related arrhythmia susceptibility in individuals carrying the major allele of this polymorphism.
PMCID: PMC3690340  PMID: 22342860
Electrocardiography; Repolarization; T wave; Epidemiology; Genetics; Polymorphism
6.  Pubertal Timing and Growth Influences Cardiometabolic Risk Factors in Adult Males and Females 
Diabetes Care  2012;35(4):850-856.
Early pubertal onset in females is associated with increased risk for adult obesity and cardiovascular disease, but whether this relationship is independent of preceding childhood growth events is unclear. Furthermore, the association between male puberty and adult disease remains unknown. To clarify the link between puberty and adult health, we evaluated the relationship between pubertal timing and risk factors for type 2 diabetes and cardiovascular disease in both males and females from a large, prospective, and randomly ascertained birth cohort from Northern Finland.
Pubertal timing was estimated based on pubertal height growth in 5,058 subjects (2,417 males and 2,641 females), and the relationship between puberty and body weight, glucose and lipid homeostasis, and blood pressure at age 31 years was evaluated with linear regression modeling.
Earlier pubertal timing associated with higher adult BMI, fasting insulin, diastolic blood pressure, and decreased HDL cholesterol in both sexes (P < 0.002) and with higher total serum cholesterol, LDL cholesterol, and triglycerides in males. The association with BMI and diastolic blood pressure remained statistically significant in both sexes, as did the association with insulin levels and HDL cholesterol concentrations in males after adjusting for covariates reflecting both fetal and childhood growth including childhood BMI.
We demonstrate independent association between earlier pubertal timing and adult metabolic syndrome-related derangements both in males and females. The connection emphasizes that the mechanisms advancing puberty may also contribute to adult metabolic disorders.
PMCID: PMC3308310  PMID: 22338106
7.  Genome-wide association study identifies multiple loci influencing human serum metabolite levels 
Nature genetics  2012;44(3):269-276.
Nuclear magnetic resonance assays allow for measurement of a wide range of metabolic phenotypes. We report here the results of a GWAS on 8,330 Finnish individuals genotyped and imputed at 7.7 million SNPs for a range of 216 serum metabolic phenotypes assessed by NMR of serum samples. We identified significant associations (P < 2.31 × 10−10) at 31 loci, including 11 for which there have not been previous reports of associations to a metabolic trait or disorder. Analyses of Finnish twin pairs suggested that the metabolic measures reported here show higher heritability than comparable conventional metabolic phenotypes. In accordance with our expectations, SNPs at the 31 loci associated with individual metabolites account for a greater proportion of the genetic component of trait variance (up to 40%) than is typically observed for conventional serum metabolic phenotypes. The identification of such associations may provide substantial insight into cardiometabolic disorders.
PMCID: PMC3605033  PMID: 22286219
8.  Association of common variants in NPPA and NPPB with circulating natriuretic peptides and blood pressure 
Nature genetics  2009;41(3):348-353.
We examined the association of common variants at the NPPA-NPPB locus with circulating concentrations of the natriuretic peptides, which have blood pressure–lowering properties. We genotyped SNPs at the NPPA-NPPB locus in 14,743 individuals of European ancestry, and identified associations of plasma atrial natriuretic peptide with rs5068 (P = 8 × 10−70), rs198358 (P = 8 × 10−30) and rs632793 (P = 2 × 10−10), and of plasma B-type natriuretic peptide with rs5068 (P = 3 × 10−12), rs198358 (P = 1 × 10−25) and rs632793 (P = 2 × 10−68). In 29,717 individuals, the alleles of rs5068 and rs198358 that showed association with increased circulating natriuretic peptide concentrations were also found to be associated with lower systolic (P = 2 × 10−6 and 6 × 10−5, respectively) and diastolic blood pressure (P = 1 × 10−6 and 5 × 10−5), as well as reduced odds of hypertension (OR = 0.85, 95% CI = 0.79–0.92, P = 4 × 10−5; OR = 0.90, 95% CI = 0.85–0.95, P = 2 × 10−4, respectively). Common genetic variants at the NPPA-NPPB locus found to be associated with circulating natriuretic peptide concentrations contribute to interindividual variation in blood pressure and hypertension.
PMCID: PMC2664511  PMID: 19219041
Hypertension  2011;58(6):1079-1085.
Clinical relevance of a genetic predisposition to elevated blood pressure was quantified during the transition from childhood to adulthood in a population-based Finnish cohort (N=2,357). Blood pressure was measured at baseline in 1980 (age 3–18 years) and in follow-ups in 1983, 1986, 2001 and 2007. Thirteen single nucleotide polymorphisms associated with blood pressure were genotyped and three genetic risk scores associated with systolic and diastolic blood pressure and their combination were derived for all participants. Effects of the genetic risk score were 0.47 mmHg for systolic and 0.53 mmHg for diastolic blood pressure (both p<0.01). The combination genetic risk score was associated with diastolic blood pressure from age 9 onwards (β=0.68 mmHg, p=0.015). Replications in 1194 participants of the Bogalusa Heart Study showed essentially similar results. The participants in the highest quintile of the combination genetic risk score had a 1.82-fold risk of hypertension in adulthood (p<0.0001) compared with the lowest quintile, independent of a family history of premature hypertension. These findings show that genetic variants are associated with preclinical blood pressure traits in childhood, individuals with several susceptibility alleles have on average a 0.5 mmHg higher blood pressure and this trajectory continues from childhood to adulthood.
PMCID: PMC3247907  PMID: 22025373
Epidemiological study; Genetic risk score; Blood Pressure; Cardiovascular disease
10.  Spray-Dried Cellulose Nanofibers as Novel Tablet Excipient 
AAPS PharmSciTech  2011;12(4):1366-1373.
The purpose of this study was to evaluate the potential of cellulose nanofibers (also referred as microfibrillated cellulose, nanocellulose, nanofibrillated, or nanofibrillar cellulose) as novel tabletting material. For this purpose, physical and mechanical properties of spray-dried cellulose nanofibers (CNF) were examined, and results were compared to those of two commercial grades of microcrystalline cellulose (MCC), Avicel PH101 and Avicel PH102, which are the most commonly and widely used direct compression excipients. Chemically, MCC and CNF are almost identical, but their physical characteristics, like mechanical properties and surface-to-volume ratio, differ remarkably. The novel material was characterized with respect to bulk and tapped as well as true density, moisture content, and flow properties. Tablets made of CNF powder and its mixtures with MCC with or without paracetamol as model compound were produced by direct compression and after wet granulation. The tensile strength of the tablets made in a series of applied pressures was determined, and yield pressure values were calculated from the measurements. With CNF, both wet granulation and direct compression were successful. During tablet compression, CNF particles were less prone to permanent deformation and had less pronounced ductile characteristics. Disintegration and dissolution studies showed slightly faster drug release from direct compression tablets with CNF, while wet granulated systems did not have any significant difference.
PMCID: PMC3225511  PMID: 22005956
cellulose nanofibers; characterization; excipient; microcrystalline cellulose; tabletting
11.  Genome-Wide Screen for Metabolic Syndrome Susceptibility Loci Reveals Strong Lipid Gene Contribution but No Evidence for Common Genetic Basis for Clustering of Metabolic Syndrome Traits 
Genome-wide association (GWA) studies have identified several susceptibility loci for metabolic syndrome (MetS) component traits, but have had variable success in identifying susceptibility loci to the syndrome as an entity. We conducted a GWA study on MetS and its component traits in four Finnish cohorts consisting of 2637 MetS cases and 7927 controls, both free of diabetes, and followed the top loci in an independent sample with transcriptome and NMR-based metabonomics data. Furthermore, we tested for loci associated with multiple MetS component traits using factor analysis and built a genetic risk score for MetS.
Methods and Results
A previously known lipid locus, APOA1/C3/A4/A5 gene cluster region (SNP rs964184), was associated with MetS in all four study samples (P=7.23×10−9 in meta-analysis). The association was further supported by serum metabolite analysis, where rs964184 associated with various VLDL, TG, and HDL metabolites (P=0.024-1.88×10−5). Twenty-two previously identified susceptibility loci for individual MetS component traits were replicated in our GWA and factor analysis. Most of these associated with lipid phenotypes and none with two or more uncorrelated MetS components. A genetic risk score, calculated as the number of alleles in loci associated with individual MetS traits, was strongly associated with MetS status.
Our findings suggest that genes from lipid metabolism pathways have the key role in the genetic background of MetS. We found little evidence for pleiotropy linking dyslipidemia and obesity to the other MetS component traits such as hypertension and glucose intolerance.
PMCID: PMC3378651  PMID: 22399527
metabolic syndrome; risk factors; genome-wide association study; meta-analysis; lipids
12.  Maternally Derived Microduplications at 15q11-q13: Implication of Imprinted Genes in Psychotic Illness 
The American journal of psychiatry  2011;168(4):408-417.
Rare copy number variants have been implicated in different neurodevelopmental disorders, with the same copy number variants often increasing risk of more than one of these phenotypes. In a discovery sample of 22 schizophrenia patients with an early onset of illness (10–15 years of age), the authors observed in one patient a maternally derived 15q11-q13 duplication overlapping the Prader-Willi/Angelman syndrome critical region. This prompted investigation of the role of 15q11-q13 duplications in psychotic illness.
The authors scanned 7,582 patients with schizophrenia or schizoaffective disorder and 41,370 comparison subjects without known psychiatric illness for copy number variants at 15q11-q13 and determined the parental origin of duplications using methylation-sensitive Southern hybridization analysis.
Duplications were found in four case patients and five comparison subjects. All four case patients had maternally derived duplications (0.05%), while only three of the five comparison duplications were maternally derived (0.007%), resulting in a significant excess of maternally derived duplications in case patients (odds ratio=7.3). This excess is compatible with earlier observations that risk for psychosis in people with Prader-Willi syndrome caused by maternal uniparental disomy is much higher than in those caused by deletion of the paternal chromosome.
These findings suggest that the presence of two maternal copies of a fragment of chromosome 15q11.2-q13.1 that overlaps with the Prader-Willi/Angelman syndrome critical region may be a rare risk factor for schizophrenia and other psychoses. Given that maternal duplications of this region are among the most consistent cytogenetic observations in autism, the findings provide further support for a shared genetic etiology between autism and psychosis.
PMCID: PMC3428917  PMID: 21324950
13.  Glucocorticoid receptor (NR3C1) gene polymorphisms and onset of alcohol abuse in adolescents 
Addiction biology  2010;16(3):510-513.
Onset of alcohol use at an early age increases the risk for later alcohol dependence. We investigated the role of the glucocorticoid receptor (GR) gene (NR3C1) in onset of alcohol use and abuse in 14-year-old adolescents (n = 4534). Several NR3C1 polymorphisms were associated with onset of alcohol drinking or drunkenness at this age. Strongest associations were observed in females, with one marker (rs244465) remaining significant after correction for multiple testing (Padj = 0.0067; odds ratio = 1.7, for drunkenness). Our data provide the first evidence that GR modulates initiation of alcohol abuse and reveal a polymorphism that might contribute to susceptibility to addiction.
PMCID: PMC3428936  PMID: 20731635
Addiction; adolescent; alcohol; glucocorticoid receptor; NR3C1; polymorphism
14.  Early Environment and Neurobehavioral Development Predict Adult Temperament Clusters 
PLoS ONE  2012;7(7):e38065.
Investigation of the environmental influences on human behavioral phenotypes is important for our understanding of the causation of psychiatric disorders. However, there are complexities associated with the assessment of environmental influences on behavior.
Methods/Principal Findings
We conducted a series of analyses using a prospective, longitudinal study of a nationally representative birth cohort from Finland (the Northern Finland 1966 Birth Cohort). Participants included a total of 3,761 male and female cohort members who were living in Finland at the age of 16 years and who had complete temperament scores. Our initial analyses (Wessman et al., in press) provide evidence in support of four stable and robust temperament clusters. Using these temperament clusters, as well as independent temperament dimensions for comparison, we conducted a data-driven analysis to assess the influence of a broad set of life course measures, assessed pre-natally, in infancy, and during adolescence, on adult temperament.
Measures of early environment, neurobehavioral development, and adolescent behavior significantly predict adult temperament, classified by both cluster membership and temperament dimensions. Specifically, our results suggest that a relatively consistent set of life course measures are associated with adult temperament profiles, including maternal education, characteristics of the family’s location and residence, adolescent academic performance, and adolescent smoking.
Our finding that a consistent set of life course measures predict temperament clusters indicate that these clusters represent distinct developmental temperament trajectories and that information about a subset of life course measures has implications for adult health outcomes.
PMCID: PMC3399831  PMID: 22815688
15.  Temperament Clusters in a Normal Population: Implications for Health and Disease 
PLoS ONE  2012;7(7):e33088.
The object of this study was to identify temperament patterns in the Finnish population, and to determine the relationship between these profiles and life habits, socioeconomic status, and health.
Methods/Principal Findings
A cluster analysis of the Temperament and Character Inventory subscales was performed on 3,761 individuals from the Northern Finland Birth Cohort 1966 and replicated on 2,097 individuals from the Cardiovascular Risk in Young Finns study. Clusters were formed using the k-means method and their relationship with 115 variables from the areas of life habits, socioeconomic status and health was examined.
Four clusters were identified for both genders. Individuals from Cluster I are characterized by high persistence, low extravagance and disorderliness. They have healthy life habits, and lowest scores in most of the measures for psychiatric disorders. Cluster II individuals are characterized by low harm avoidance and high novelty seeking. They report the best physical capacity and highest level of income, but also high rate of divorce, smoking, and alcohol consumption. Individuals from Cluster III are not characterized by any extreme characteristic. Individuals from Cluster IV are characterized by high levels of harm avoidance, low levels of exploratory excitability and attachment, and score the lowest in most measures of health and well-being.
This study shows that the temperament subscales do not distribute randomly but have an endogenous structure, and that these patterns have strong associations to health, life events, and well-being.
PMCID: PMC3399883  PMID: 22815673
16.  Phenotype mining in CNV carriers from a population cohort† 
Human Molecular Genetics  2011;20(13):2686-2695.
Phenotype mining is a novel approach for elucidating the genetic basis of complex phenotypic variation. It involves a search of rich phenotype databases for measures correlated with genetic variation, as identified in genome-wide genotyping or sequencing studies. An initial implementation of phenotype mining in a prospective unselected population cohort, the Northern Finland 1966 Birth Cohort (NFBC1966), identifies neurodevelopment-related traits—intellectual deficits, poor school performance and hearing abnormalities—which are more frequent among individuals with large (>500 kb) deletions than among other cohort members. Observation of extensive shared single nucleotide polymorphism haplotypes around deletions suggests an opportunity to expand phenotype mining from cohort samples to the populations from which they derive.
PMCID: PMC3110003  PMID: 21505072
17.  Population frequency of myotonic dystrophy: higher than expected frequency of myotonic dystrophy type 2 (DM2) mutation in Finland 
Myotonic dystrophy (DM) is the most common adult-onset muscular dystrophy with an estimated prevalence of 1/8000. There are two genetically distinct types, DM1 and DM2. DM2 is generally milder with more phenotypic variability than the classic DM1. Our previous data on co-segregation of heterozygous recessive CLCN1 mutations in DM2 patients indicated a higher than expected DM2 prevalence. The aim of this study was to determine the DM2 and DM1 frequency in the general population, and to explore whether the DM2 mutation functions as a modifier in other neuromuscular diseases (NMD) to account for unexplained phenotypic variability. We genotyped 5535 Finnish individuals: 4532 normal blood donors, 606 patients with various non-myotonic NMD, 221 tibial muscular dystrophy patients and their 176 healthy relatives for the DM2 and DM1 mutations. We also genotyped an Italian idiopathic non-myotonic proximal myopathy cohort (n=93) for the DM2 mutation. In 5496 samples analyzed for DM2, we found three DM2 mutations and two premutations. In 5511 samples analyzed for DM1, we found two DM1 mutations and two premutations. In the Italian cohort, we identified one patient with a DM2 mutation. We conclude that the DM2 mutation frequency is significantly higher in the general population (1/1830; P-value=0.0326) than previously estimated. The identification of DM2 mutations in NMD patients with clinical phenotypes not previously associated with DM2 is of particular interest and is in accord with the high overall prevalence. On the basis of our results, DM2 appears more frequent than DM1, with most DM2 patients currently undiagnosed with symptoms frequently occurring in the elderly population.
PMCID: PMC3137497  PMID: 21364698
myotonic dystrophy; mutation frequency; prevalence; population
18.  TTC12-ANKK1-DRD2 and CHRNA5-CHRNA3-CHRNB4 influence different pathways leading to smoking behaviour from adolescence to mid-adulthood 
Biological psychiatry  2010;69(7):650-660.
CHRNA5-CHRNA3-CHRNB4 and TTC12-ANKK1-DRD2 gene-clusters influence smoking behavior. Our aim was to test developmental changes in their effects as well as the interplays between them and with non-genetic factors.
Participants included 4,762 subjects from a general population based prospective Northern Finland 1966 Birth Cohort (NFBC 1966). Smoking behavior was collected at age 14 and 31 years(y). Information on maternal smoking, socio-economic status, and novelty seeking were also collected. Structural equation modeling was used to construct an integrative etiological model including genetic and non-genetic factors.
Several SNPs in both gene-clusters were significantly associated with smoking. The most significant were in CHRNA3 (rs1051730, P=1.1×10−5) and in TTC12 (rs10502172, P=9.1×10−6). CHRNA3-rs1051730[A] was more common among heavy/regular smokers than non-smokers with similar effect-sizes at age 14y [OR(95%CI):1.27(1.06–1.52)] and 31y [1.28(1.13–1.44)]. TTC12-rs10502172[G] was more common among smokers than non-smokers with stronger association at 14y [1.33(1.11–1.60)] than 31y [1.14(1.02–1.28)]. In adolescence, carriers of three-four risk alleles at either CHRNA3-rs1051730 or TTC12-rs10502172 had almost 3-fold odds of smoking regularly than subjects with no risk alleles. TTC12-rs10502172 effect on smoking in adulthood was mediated by its effect on smoking in adolescence and via novelty seeking. Effect of CHRNA3-rs1051730 on smoking in adulthood was direct.
TTC12-ANKK1-DRD2s seemed to influence smoking behavior mainly in adolescence and its effect is partially mediated by personality characteristics promoting drug-seeking behavior. In contrast, CHRNA5-CHRNA3-CHRNB4 is involved in the transition towards heavy smoking in mid-adulthood and in smoking persistence. Factors related to familial and social disadvantages were strong independent predictors of smoking.
PMCID: PMC3058144  PMID: 21168125
TTC12; ANKK1; DRD2; CHRNA5; CHRNA3; CHRNB4; nicotine; gene; adolescence; smoking
19.  Meta-analysis of genome-wide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque 
Bis, Joshua C. | Kavousi, Maryam | Franceschini, Nora | Isaacs, Aaron | Abecasis, Gonçalo R | Schminke, Ulf | Post, Wendy | Smith, Albert V. | Cupples, L. Adrienne | Markus, Hugh S | Schmidt, Reinhold | Huffman, Jennifer E. | Lehtimäki, Terho | Baumert, Jens | Münzel, Thomas | Heckbert, Susan R. | Dehghan, Abbas | North, Kari | Oostra, Ben | Bevan, Steve | Stoegerer, Eva-Maria | Hayward, Caroline | Raitakari, Olli | Meisinger, Christa | Schillert, Arne | Sanna, Serena | Völzke, Henry | Cheng, Yu-Ching | Thorsson, Bolli | Fox, Caroline S. | Rice, Kenneth | Rivadeneira, Fernando | Nambi, Vijay | Halperin, Eran | Petrovic, Katja E. | Peltonen, Leena | Wichmann, H. Erich | Schnabel, Renate B. | Dörr, Marcus | Parsa, Afshin | Aspelund, Thor | Demissie, Serkalem | Kathiresan, Sekar | Reilly, Muredach P. | Uitterlinden, Andre | Couper, David J. | Sitzer, Matthias | Kähönen, Mika | Illig, Thomas | Wild, Philipp S. | Orru, Marco | Lüdemann, Jan | Shuldiner, Alan R. | Eiriksdottir, Gudny | White, Charles C. | Rotter, Jerome I. | Hofman, Albert | Seissler, Jochen | Zeller, Tanja | Usala, Gianluca | Ernst, Florian | Launer, Lenore J. | D'Agostino, Ralph B. | O'Leary, Daniel H. | Ballantyne, Christie | Thiery, Joachim | Ziegler, Andreas | Lakatta, Edward G. | Chilukoti, Ravi Kumar | Harris, Tamara B. | Wolf, Philip A. | Psaty, Bruce M. | Polak, Joseph F | Li, Xia | Rathmann, Wolfgang | Uda, Manuela | Boerwinkle, Eric | Klopp, Norman | Schmidt, Helena | Wilson, James F | Viikari, Jorma | Koenig, Wolfgang | Blankenberg, Stefan | Newman, Anne B. | Witteman, Jacqueline | Heiss, Gerardo | van Duijn, Cornelia | Scuteri, Angelo | Homuth, Georg | Mitchell, Braxton D. | Gudnason, Vilmundur | O’Donnell, Christopher J.
Nature Genetics  2011;43(10):940-947.
PMCID: PMC3257519  PMID: 21909108
genome-wide association study; genetic epidemiology; genetics; subclinical atherosclerosis; carotid intima media thickness; cardiovascular disease; cohort study; meta-analysis; risk
20.  NordicDB: a Nordic pool and portal for genome-wide control data 
European Journal of Human Genetics  2010;18(12):1322-1326.
A cost-efficient way to increase power in a genetic association study is to pool controls from different sources. The genotyping effort can then be directed to large case series. The Nordic Control database, NordicDB, has been set up as a unique resource in the Nordic area and the data are available for authorized users through the web portal ( The current version of NordicDB pools together high-density genome-wide SNP information from ∼5000 controls originating from Finnish, Swedish and Danish studies and shows country-specific allele frequencies for SNP markers. The genetic homogeneity of the samples was investigated using multidimensional scaling (MDS) analysis and pairwise allele frequency differences between the studies. The plot of the first two MDS components showed excellent resemblance to the geographical placement of the samples, with a clear NW–SE gradient. We advise researchers to assess the impact of population structure when incorporating NordicDB controls in association studies. This harmonized Nordic database presents a unique genome-wide resource for future genetic association studies in the Nordic countries.
PMCID: PMC3002853  PMID: 20664631
common controls; genome-wide data; Nordic Control Database; population stratification
21.  Gene variants associated with schizophrenia in a Norwegian genome-wide study are replicated in a large European cohort 
Journal of psychiatric research  2010;44(12):748-753.
We have performed a genome-wide association study (GWAS) of schizophrenia in a Norwegian discovery sample of 201 cases and 305 controls (TOP study) with a focused replication analysis in a larger European sample of 2663 cases and 13,780 control subjects (SGENE-plus study). Firstly, the discovery sample was genotyped with Affymetrix Genome-Wide Human SNP Array 6.0 and 572,888 markers were tested for schizophrenia association. No SNPs in the discovery sample attained genome-wide significance (P < 8.7 × 10−8). Secondly, based on the GWAS data, we selected 1000 markers with the lowest P values in the discovery TOP sample, and tested these (or HapMap-based surrogates) for association in the replication sample. Sixteen loci were associated with schizophrenia (nominal P value < 0.05 and concurring OR) in the replication sample. As a next step, we performed a combined analysis of the findings from these two studies, and the strongest evidence for association with schizophrenia was provided for markers rs7045881 on 9p21, rs433598 on 16p12 and rs10761482 on 10q21. The markers are located in PLAA, ACSM1 and ANK3, respectively. PLAA has not previously been described as a susceptibility gene, but 9p21 is implied as a schizophrenia linkage region. ACSM1 has been identified as a susceptibility gene in a previous schizophrenia GWAS study. The association of ANK3 with schizophrenia is intriguing in light of recent associations of ANK3 with bipolar disorder, thereby supporting the hypothesis of an overlap in genetic susceptibility between these psychopathological entities.
PMCID: PMC3224994  PMID: 20185149
Schizophrenia; Genome-wide association study; PLAA; ACSM1; ANK3; Psychiatric genetics
22.  Genetic Association and Interaction Analysis of USF1 and APOA5 on Lipid Levels and Atherosclerosis 
USF1 is a ubiquitous transcription factor governing the expression of numerous genes of lipid and glucose metabolism. APOA5 is a well-established candidate gene regulating triglyceride (TG) levels and has been identified as a downstream target of upstream stimulatory factor. No detailed studies about the effect of APOA5 on atherosclerotic lesion formation have been conducted, nor has its potential interaction with USF1 been examined.
Methods and Results
We analyzed allelic variants of USF1 and APOA5 in families (n=516) ascertained for atherogenic dyslipidemia and in an autopsy series of middle-aged men (n=300) with precise quantitative measurements of atherosclerotic lesions. The impact of previously associated APOA5 variants on TGs was observed in the dyslipidemic families, and variant rs3135506 was associated with size of fibrotic aortic lesions in the autopsy series. The USF1 variant rs2516839, associated previously with atherosclerotic lesions, showed an effect on TGs in members of the dyslipidemic families with documented coronary artery disease. We provide preliminary evidence of gene-gene interaction between these variants in an autopsy series with a fibrotic lesion area in the abdominal aorta (P=0.0028), with TGs in dyslipidemic coronary artery disease subjects (P=0.03), and with high-density lipoprotein cholesterol (P=0.008) in a large population cohort of coronary artery disease patients (n=1065) in which the interaction for TGs was not replicated.
Our findings in these unique samples reinforce the roles of APOA5 and USF1 variants on cardiovascular phenotypes and suggest that both genes contribute to lipid levels and aortic atherosclerosis individually and possibly through epistatic effects.
PMCID: PMC3224996  PMID: 19910639
genes; USF1; APOA5; lipids; atherosclerosis; epistasis
23.  Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci 
Nature genetics  2010;42(2):123-127.
To identify susceptibility loci for ankylosing spondylitis, we undertook a genome-wide association study in 2,053 unrelated ankylosing spondylitis cases among people of European descent and 5,140 ethnically matched controls, with replication in an independent cohort of 898 ankylosing spondylitis cases and 1,518 controls. Cases were genotyped with Illumina HumHap370 genotyping chips. In addition to strong association with the major histocompatibility complex (MHC; P < 10−800), we found association with SNPs in two gene deserts at 2p15 (rs10865331; combined P = 1.9 × 10−19) and 21q22 (rs2242944; P = 8.3 × 10−20), as well as in the genes ANTXR2 (rs4333130; P = 9.3 × 10−8) and IL1R2 (rs2310173; P = 4.8 × 10−7). We also replicated previously reported associations at IL23R (rs11209026; P = 9.1 × 10−14) and ERAP1 (rs27434; P = 5.3 × 10−12). This study reports four genetic loci associated with ankylosing spondylitis risk and identifies a major role for the interleukin (IL)-23 and IL-1 cytokine pathways in disease susceptibility.
PMCID: PMC3224997  PMID: 20062062
24.  The Effect of Chromosome 9p21 Variants on Cardiovascular Disease May Be Modified by Dietary Intake: Evidence from a Case/Control and a Prospective Study 
PLoS Medicine  2011;8(10):e1001106.
Ron Do and colleagues find that a prudent diet high in raw vegetables may modify the increased genetic risk of cardiovascular disease conferred by the chromosome 9p21 SNP.
One of the most robust genetic associations for cardiovascular disease (CVD) is the Chromosome 9p21 region. However, the interaction of this locus with environmental factors has not been extensively explored. We investigated the association of 9p21 with myocardial infarction (MI) in individuals of different ethnicities, and tested for an interaction with environmental factors.
Methods and Findings
We genotyped four 9p21 SNPs in 8,114 individuals from the global INTERHEART study. All four variants were associated with MI, with odds ratios (ORs) of 1.18 to 1.20 (1.85×10−8≤p≤5.21×10−7). A significant interaction (p = 4.0×10−4) was observed between rs2383206 and a factor-analysis-derived “prudent” diet pattern score, for which a major component was raw vegetables. An effect of 9p21 on MI was observed in the group with a low prudent diet score (OR = 1.32, p = 6.82×10−7), but the effect was diminished in a step-wise fashion in the medium (OR = 1.17, p = 4.9×10−3) and high prudent diet scoring groups (OR = 1.02, p = 0.68) (p = 0.014 for difference). We also analyzed data from 19,129 individuals (including 1,014 incident cases of CVD) from the prospective FINRISK study, which used a closely related dietary variable. In this analysis, the 9p21 risk allele demonstrated a larger effect on CVD risk in the groups with diets low or average for fresh vegetables, fruits, and berries (hazard ratio [HR] = 1.22, p = 3.0×10−4, and HR = 1.35, p = 4.1×10−3, respectively) compared to the group with high consumption of these foods (HR = 0.96, p = 0.73) (p = 0.0011 for difference). The combination of the least prudent diet and two copies of the risk allele was associated with a 2-fold increase in risk for MI (OR = 1.98, p = 2.11×10−9) in the INTERHEART study and a 1.66-fold increase in risk for CVD in the FINRISK study (HR = 1.66, p = 0.0026).
The risk of MI and CVD conferred by Chromosome 9p21 SNPs appears to be modified by a prudent diet high in raw vegetables and fruits.
Please see later in the article for the Editors' Summary
Editors' Summary
Cardiovascular diseases (CVDs)—diseases that affect the heart and/or the blood vessels—are a leading cause of illness and death worldwide. In the United States, for example, the leading cause of death is coronary heart disease, a CVD in which narrowing of the heart's blood vessels by fatty deposits slows the blood supply to the heart and may eventually cause a heart attack (myocardial infarction, or MI); the third leading cause of death in the US is stroke, a CVD in which the brain's blood supply is interrupted. Environmental factors such as diet, physical activity, and smoking alter a person's risk of developing CVD. In addition, certain genetic variants (alterations in the DNA that forms the body's blueprint; DNA is packed into structures called chromosomes) alter the risk of developing CVD and are passed from parent to child. Thus, in CVD, as in most common diseases, both genetics and the environment play a role.
Why Was This Study Done?
Recent studies have identified several genetic variants that are associated with an increased risk of developing CVD. One of the most robust of these genetic associations is a cluster of single nucleotide polymorphisms (SNPs, differences in a single DNA building block) in a chromosomal region (locus) called 9p21. So far, this association has been mainly studied in European populations. Moreover, the interaction of this locus with environmental factors has not been extensively studied. A better understanding of how 9p21 variants affect CVD risk in people of different ethnicities and of the interaction between this locus and environmental factors could allow the development of targeted strategies for the prevention of CVD. In this study, the researchers investigate the association of 9p21 risk variants with CVD in people of different ethnicities and test for an interaction between this locus and environmental factors.
What Did the Researchers Do and Find?
The researchers assessed four 9p21 SNPs in people enrolled in the INTERHEART study, a global retrospective case-control study that investigated potential MI risk factors by comparing people who had had an acute non-fatal MI with similar people without heart disease. All four SNP risk variants increased the risk of MI by about a fifth. However, the effect of the SNPs on MI was influenced by the “prudent” diet pattern score of the INTERHEART participants, a score that includes fresh fruit and vegetable intake as recorded in food frequency questionnaires. That is, the risk of MI in people carrying SNP risk variants was influenced by their diet. The strongest interaction was seen with an SNP called rs2383206, but although rs2383206 carriers who ate a diet poor in fruits and vegetables had a higher risk of MI than people with a similar diet who did not carry this SNP, rs2383206 carriers and non-carriers who ate a fruit- and vegetable-rich diet had a comparable MI risk. Overall, the combination of the least “prudent” diet and two copies of the risk variant (human cells contain two complete sets of chromosomes) was associated with a two-fold increase in risk for MI in the INTERHEART study. Additionally, data collected in the FINRISK study, which characterized healthy individuals living in Finland at baseline and then followed them to see whether they developed CVD, revealed a similar interaction between diet and 9p21 SNPs.
What Do These Findings Mean?
These findings suggest that the risk of CVD conferred by chromosome 9p21 SNPs may be influenced by diet in multiple ethnic groups. Importantly, they suggest that the deleterious effect of 9p21 SNPs on CVD might be mitigated by consuming a diet rich in fresh fruits and vegetables. The accuracy of these findings may be affected by recall bias in the INTERHEART study (that is, some people may not have remembered their diet accurately) and by the small number of CVD cases in the FINRISK study. Nevertheless, these findings suggest that gene–environment interactions are important drivers of CVD, and they raise the possibility that a sound diet can mediate the effects of 9p21 SNPs.
Additional Information
Please access these websites via the online version of this summary at
The American Heart Association provides information about many types of cardiovascular disease for patients, caregivers, and professionals and tips on keeping the heart healthy
The UK National Health Service Choices website provides information about cardiovascular disease and stroke
Information is available from the British Heart Foundation on heart disease and keeping the heart healthy
The US National Heart Lung and Blood Institute provides information on a wide range of cardiovascular diseases
MedlinePlus provides links to many other sources of information on heart diseases, vascular diseases, and stroke (in English and Spanish)
The US Centers for Disease Control and Prevention has a simple fact sheet on gene-environment interactions; the US National Institute of Environmental Health Sciences provides links to other information on gene-environment interactions
More information is available on the INTERHEART study and on the FINRISK study
PMCID: PMC3191151  PMID: 22022235
Nature  2010;468(7327):1061-1066.
Impulsivity, describing action without foresight, is an important feature of several psychiatric diseases, suicidality and violent behavior. The complex origins of impulsivity hinder identification of the genes influencing both it and diseases with which it is associated. We performed exon-centric sequencing of impulsive individuals in a founder population, targeting fourteen genes belonging to the serotonin and dopamine domain. A stop codon in HTR2B that is common (MAF >1%) but exclusive to Finns was identified. Expression of the gene in the human brain was assessed, as well as the molecular functionality of the stop codon that was associated with psychiatric diseases marked by impulsivity in both population and family-based analyses. Knockout of Htr2b increased impulsive behaviors in mice, indicative of predictive validity. Our study shows the potential for identifying and tracing effects of rare alleles in complex behavioral phenotypes using founder populations, and suggests a role for HTR2B in impulsivity.
PMCID: PMC3183507  PMID: 21179162

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