Phenotype Harmonization in the GLIDE2 Oral Health Genomics Consortium.

Genetic risk factors play important roles in the etiology of oral, dental, and craniofacial diseases. Identifying the relevant risk loci and understanding their molecular biology could highlight new prevention and management avenues. Our current understanding of oral health genomics suggests that dental caries and periodontitis are polygenic diseases, and very large sample sizes and informative phenotypic measures are required to discover signals and adequately map associations across the human genome. In this article, we introduce the second wave of the Gene-Lifestyle Interactions and Dental Endpoints consortium (GLIDE2) and discuss relevant data analytics challenges, opportunities, and applications. In this phase, the consortium comprises a diverse, multiethnic sample of over 700,000 participants from 21 studies contributing clinical data on dental caries experience and periodontitis. We outline the methodological challenges of combining data from heterogeneous populations, as well as the data reduction problem in resolving detailed clinical examination records into tractable phenotypes, and describe a strategy that addresses this. Specifically, we propose a 3-tiered phenotyping approach aimed at leveraging both the large sample size in the consortium and the detailed clinical information available in some studies, wherein binary, severity-encompassing, and "precision," data-driven clinical traits are employed. As an illustration of the use of data-driven traits across multiple cohorts, we present an application of dental caries experience data harmonization in 8 participating studies (N = 55,143) using previously developed permanent dentition tooth surface-level dental caries pattern traits. We demonstrate that these clinical patterns are transferable across multiple cohorts, have similar relative contributions within each study, and thus are prime targets for genetic interrogation in the expanded and diverse multiethnic sample of GLIDE2. We anticipate that results from GLIDE2 will decisively advance the knowledge base of mechanisms at play in oral, dental, and craniofacial health and disease and further catalyze international collaboration and data and resource sharing in genomics research.

Heritability of Caries Scores, Trajectories, and Disease Subtypes.

Previous studies report that dental caries is partially heritable, but there is uncertainty in the magnitude of genetic effects and little understanding of how genetic factors might influence caries progression or caries subtypes. This study aimed to estimate the relative importance of genetic and environmental factors in the etiology of different caries outcomes using a twin-based design. Analysis included up to 41,678 twins in the Swedish Twin Register aged 7 to 97 y, and dental data were obtained from preexisting dental records. The outcome measures were 1) summary indices of caries experience, 2) parameters representing trajectory in caries progression derived from longitudinal modeling, and 3) caries scores in groups of biologically similar tooth surfaces derived from hierarchical clustering of tooth surfaces (termed caries clusters). Additive genetic factors explained between 49.1% and 62.7% of variation in caries scores and between 50.0% and 60.5% of variation in caries trajectories. Seven caries clusters were identified, which had estimates of heritability lying between 41.9% and 54.3%. Shared environmental factors were important for only some of these clusters and explained 16% of variation in fissure caries in molar teeth but little variation in other clusters of caries presentation. The genetic factors influencing these clusters were only partially overlapping, suggesting that different biological processes are important in different groups of tooth surfaces and that innate liability to some patterns of caries presentation may partially explain why groups of tooth surfaces form clusters within the mouth. These results provide 1) improved quantification of genetic factors in the etiology of caries and 2) new data about the role of genetics in terms of longitudinal changes in caries status and specific patterns of disease presentation, and they may help lay the foundations for personalized interventions in the future.

The impact of education, country, race and ethnicity on the self-report of postpartum depression using the Edinburgh Postnatal Depression Scale.

BACKGROUND: Universal screening for postpartum depression is recommended in many countries. Knowledge of whether the disclosure of depressive symptoms in the postpartum period differs across cultures could improve detection and provide new insights into the pathogenesis. Moreover, it is a necessary step to evaluate the universal use of screening instruments in research and clinical practice. In the current study we sought to assess whether the Edinburgh Postnatal Depression Scale (EPDS), the most widely used screening tool for postpartum depression, measures the same underlying construct across cultural groups in a large international dataset. METHOD: Ordinal regression and measurement invariance were used to explore the association between culture, operationalized as education, ethnicity/race and continent, and endorsement of depressive symptoms using the EPDS on 8209 new mothers from Europe and the USA. RESULTS: Education, but not ethnicity/race, influenced the reporting of postpartum depression [difference between robust comparative fit indexes (∆*CFI) 0.01), but not between European countries (∆*CFI < 0.01). CONCLUSIONS: Investigators and clinicians should be aware of the potential differences in expression of phenotype of postpartum depression that women of different educational backgrounds may manifest. The increasing cultural heterogeneity of societies together with the tendency towards globalization requires a culturally sensitive approach to patients, research and policies, that takes into account, beyond rhetoric, the context of a person's experiences and the context in which the research is conducted.

Somatic, positive and negative domains of the Center for Epidemiological Studies Depression (CES-D) scale: a meta-analysis of genome-wide association studies.

BACKGROUND: Major depressive disorder (MDD) is moderately heritable, however genome-wide association studies (GWAS) for MDD, as well as for related continuous outcomes, have not shown consistent results. Attempts to elucidate the genetic basis of MDD may be hindered by heterogeneity in diagnosis. The Center for Epidemiological Studies Depression (CES-D) scale provides a widely used tool for measuring depressive symptoms clustered in four different domains which can be combined together into a total score but also can be analysed as separate symptom domains. METHOD: We performed a meta-analysis of GWAS of the CES-D symptom clusters. We recruited 12 cohorts with the 20- or 10-item CES-D scale (32 528 persons). RESULTS: One single nucleotide polymorphism (SNP), rs713224, located near the brain-expressed melatonin receptor (MTNR1A) gene, was associated with the somatic complaints domain of depression symptoms, with borderline genome-wide significance (p discovery = 3.82 × 10-8). The SNP was analysed in an additional five cohorts comprising the replication sample (6813 persons). However, the association was not consistent among the replication sample (p discovery+replication = 1.10 × 10-6) with evidence of heterogeneity. CONCLUSIONS: Despite the effort to harmonize the phenotypes across cohorts and participants, our study is still underpowered to detect consistent association for depression, even by means of symptom classification. On the contrary, the SNP-based heritability and co-heritability estimation results suggest that a very minor part of the variation could be captured by GWAS, explaining the reason of sparse findings.

Heritability and confirmation of genetic association studies for childhood asthma in twins.

BACKGROUND: Although the genetics of asthma has been extensively studied using both quantitative and molecular genetic analysis methods, both approaches lack studies specific to the childhood phenotype and including other allergic diseases. This study aimed to give specific estimates for the heritability of childhood asthma and other allergic diseases, to attempt to replicate findings from genomewide association studies (GWAS) for childhood asthma and to test the same variants against other allergic diseases. METHODS: In a cohort of 25 306 Swedish twins aged 9 or 12 years, data on asthma were available from parental interviews and population-based registers. The interviews also inquired about wheeze, hay fever, eczema, and food allergy. Through structural equation modeling, the heritability of all phenotypes was calculated. A subset of 10 075 twins was genotyped for 16 single nucleotide polymorphisms (SNPs) selected from previous GWAS; these were first tested for association with asthma and significant findings also against the other allergic diseases. RESULTS: The heritability of any childhood asthma was 0.82 (95% CI 0.79-0.85). For the other allergic diseases, the range was approximately 0.60-0.80. Associations for six SNPs with asthma were replicated, including rs2305480 in the GSDMB gene (OR 0.80, 95% CI 0.74-0.86, P = 1.5*10(-8) ; other significant associations all below P = 3.5*10(-4) ). Of these, only rs3771180 in IL1RL1 was associated with any other allergic disease (for hay fever, OR 0.64, 95% CI 0.53-0.77, P = 2.5*10(-6) ). CONCLUSION: Asthma and allergic diseases of childhood are highly heritable, and these high-risk genetic variants associated specifically with childhood asthma, except for one SNP shared with hay fever.

A genome-wide association study of kynurenic acid in cerebrospinal fluid: implications for psychosis and cognitive impairment in bipolar disorder.

Elevated cerebrospinal fluid (CSF) levels of the glia-derived N-methyl-D-aspartic acid receptor antagonist kynurenic acid (KYNA) have consistently been implicated in schizophrenia and bipolar disorder. Here, we conducted a genome-wide association study based on CSF KYNA in bipolar disorder and found support for an association with a common variant within 1p21.3. After replication in an independent cohort, we linked this genetic variant-associated with reduced SNX7 expression-to positive psychotic symptoms and executive function deficits in bipolar disorder. A series of post-mortem brain tissue and in vitro experiments suggested SNX7 downregulation to result in a caspase-8-driven activation of interleukin-1ß and a subsequent induction of the brain kynurenine pathway. The current study demonstrates the potential of using biomarkers in genetic studies of psychiatric disorders, and may help to identify novel drug targets in bipolar disorder.

Intellectual disability and cognitive ability in Darier disease: Swedish nation-wide study.

BACKGROUND: Darier disease is an autosomal dominant skin disorder caused by mutations in the ATP2A2 gene. Anecdotal reports suggest a relationship between Darier disease and intellectual disabilities, but these reports are based on small clinical samples and limited by absence of control populations. OBJECTIVES: To examine the risk of intellectual disability and subclinical impairments in cognitive ability in Darier disease. METHODS: We conducted a matched cohort study based on Swedish Population-, Patient- and Conscript Registers. The risk of being diagnosed with intellectual disability was estimated in 770 individuals with Darier disease, compared with matched comparison individuals without Darier disease. Associations were examined with risk ratios from conditional logistic regressions. In addition, we analysed test-based cognitive ability data (i.e. IQ data) from the Swedish conscript examination, for a subset of patients without diagnosed intellectual disability. RESULTS: Individuals with Darier disease had a sixfold increased risk of being diagnosed with intellectual disability (risk ratio 6.2, 95% confidence interval 3.1-12.4). For conscripted individuals with Darier disease but no diagnosed intellectual disability, mean cognitive ability scores were about half a standard deviation lower than for comparison subjects. CONCLUSIONS: Darier disease is associated with intellectual disability and subclinical impairments in cognitive ability. The Darier-causing mutations merit further attention in molecular genetic research on intellectual disability and cognitive ability.

Copy number variation in schizophrenia in Sweden.

Schizophrenia (SCZ) is a highly heritable neuropsychiatric disorder of complex genetic etiology. Previous genome-wide surveys have revealed a greater burden of large, rare copy number variations (CNVs) in SCZ cases and identified multiple rare recurrent CNVs that increase risk of SCZ although with incomplete penetrance and pleiotropic effects. Identification of additional recurrent CNVs and biological pathways enriched for SCZ CNVs requires greater sample sizes. We conducted a genome-wide survey for CNVs associated with SCZ using a Swedish national sample (4719 cases and 5917 controls). High-confidence CNV calls were generated using genotyping array intensity data, and their effect on risk of SCZ was measured. Our data confirm increased burden of large, rare CNVs in SCZ cases as well as significant associations for recurrent 16p11.2 duplications, 22q11.2 deletions and 3q29 deletions. We report a novel association for 17q12 duplications (odds ratio=4.16, P=0.018), previously associated with autism and mental retardation but not SCZ. Intriguingly, gene set association analyses implicate biological pathways previously associated with SCZ through common variation and exome sequencing (calcium channel signaling and binding partners of the fragile X mental retardation protein). We found significantly increased burden of the largest CNVs (>500 kb) in genes present in the postsynaptic density, in genomic regions implicated via SCZ genome-wide association studies and in gene products localized to mitochondria and cytoplasm. Our findings suggest that multiple lines of genomic inquiry--genome-wide screens for CNVs, common variation and exonic variation--are converging on similar sets of pathways and/or genes.

Genetic factors may play a prominent role in the development of coronary heart disease dependent on important environmental factors.

OBJECTIVE: The aim of the study was to examine whether various lifestyle factors modify genetic influences on coronary heart disease (CHD). DESIGN: The effect of lifestyle factors [including smoking, sedentary lifestyle, alcohol intake and body mass index (BMI)] on risk of CHD was evaluated via Cox regression models in a twin study of gene-environment interaction. Using structure equation modelling, we estimated genetic variance of CHD dependent on lifestyle factors. SUBJECTS: In total, 51 065 same-sex twins from 25 715 twin pairs born before 1958 and registered in the Swedish Twin Registry were eligible for this study. During the 40-year follow-up, 7264 incident CHD events were recorded. RESULTS: Smoking, sedentary lifestyle and above average BMI were significantly associated with increased CHD incidence. The heritability of CHD decreased with increasing age, as well as with increasing levels of BMI, in both men and women. CONCLUSIONS: The difference in the genetic component of CHD as a function of BMI suggests that genetic factors may play a more prominent role for disease development in the absence of important environmental factors. Increased knowledge of gene-environment interactions will be important for a full understanding of the aetiology of CHD.

Multifactorial analysis of changes in body mass index across the adult life course: a study with 65 years of follow-up.

BACKGROUND: Although the negative consequences on health of being obese are well known, most adults gain weight across the lifespan. The general increase in body mass index (BMI) is mainly considered to originate from behavioral and environmental changes; however, few studies have evaluated the influence of these factors on change in BMI in the presence of genetic risk. We aimed to study the influence of multifactorial causes of change in BMI, over 65 years. METHODS AND FINDINGS: Totally, 6130 participants from TwinGene, who had up to five assessments, and 536 from the Swedish Adoption/Twin Study of Aging, who had up to 12 assessments, ranging over 65 years were included. The influence of lifestyle factors, birth cohort, cardiometabolic diseases and an individual obesity genetic risk score (OGRS) based on 32 single nucleotide polymorphisms on change in BMI was evaluated with a growth model. For both sexes, BMI increased from early adulthood to age of 65 years, after which the increase leveled off; BMI declined after age of 80 years. A higher OGRS, birth after 1925 and cardiometabolic diseases were associated with higher average BMI and a steeper increase in BMI prior to 65 years of age. Among men, few factors were identified that influence BMI trajectories in late life, whereas for women type 2 diabetes mellitus and dementia were associated with a steeper decrease in BMI after the age of 65 years. CONCLUSIONS: There are two turning points in BMI in late adulthood, one at the age of 65 years and one at the age 80 years. Factors associated with an increase in BMI in midlife were not associated with an increase in BMI after the age of 65 years. These findings indicate that the causes and consequences of change in BMI differ across the lifespan. Current health recommendations need to be adjusted accordingly.

Detecting large copy number variants using exome genotyping arrays in a large Swedish schizophrenia sample.

Although copy number variants (CNVs) are important in genomic medicine, CNVs have not been systematically assessed for many complex traits. Several large rare CNVs increase risk for schizophrenia (SCZ) and autism and often demonstrate pleiotropic effects; however, their frequencies in the general population and other complex traits are unknown. Genotyping large numbers of samples is essential for progress. Large cohorts from many different diseases are being genotyped using exome-focused arrays designed to detect uncommon or rare protein-altering sequence variation. Although these arrays were not designed for CNV detection, the hybridization intensity data generated in each experiment could, in principle, be used for gene-focused CNV analysis. Our goal was to evaluate the extent to which CNVs can be detected using data from one particular exome array (the Illumina Human Exome Bead Chip). We genotyped 9100 Swedish subjects (3962 cases with SCZ and 5138 controls) using both standard genome-wide association study (GWAS) and exome arrays. In comparison with CNVs detected using GWAS arrays, we observed high sensitivity and specificity for detecting genic CNVs 400 kb including known pathogenic CNVs along with replicating the literature finding that cases with SCZ had greater enrichment for genic CNVs. Our data confirm the association of SCZ with 16p11.2 duplications and 22q11.2 deletions, and suggest a novel association with deletions at 11q12.2. Our results suggest the utility of exome-focused arrays in surveying large genic CNVs in very large samples; and thereby open the door for new opportunities such as conducting well-powered CNV assessment and comparisons between different diseases. The use of a single platform also minimizes potential confounding factors that could impact accurate detection.

Common SNPs explain some of the variation in the personality dimensions of neuroticism and extraversion.

The personality traits of neuroticism and extraversion are predictive of a number of social and behavioural outcomes and psychiatric disorders. Twin and family studies have reported moderate heritability estimates for both traits. Few associations have been reported between genetic variants and neuroticism/extraversion, but hardly any have been replicated. Moreover, the ones that have been replicated explain only a small proportion of the heritability (<~2%). Using genome-wide single-nucleotide polymorphism (SNP) data from ~12,000 unrelated individuals we estimated the proportion of phenotypic variance explained by variants in linkage disequilibrium with common SNPs as 0.06 (s.e. = 0.03) for neuroticism and 0.12 (s.e. = 0.03) for extraversion. In an additional series of analyses in a family-based sample, we show that while for both traits ~45% of the phenotypic variance can be explained by pedigree data (that is, expected genetic similarity) one third of this can be explained by SNP data (that is, realized genetic similarity). A part of the so-called 'missing heritability' has now been accounted for, but some of the reported heritability is still unexplained. Possible explanations for the remaining missing heritability are that: (i) rare variants that are not captured by common SNPs on current genotype platforms make a major contribution; and/ or (ii) the estimates of narrow sense heritability from twin and family studies are biased upwards, for example, by not properly accounting for nonadditive genetic factors and/or (common) environmental factors.

Genome-wide association study in a Swedish population yields support for greater CNV and MHC involvement in schizophrenia compared with bipolar disorder.

Schizophrenia (SCZ) and bipolar disorder (BD) are highly heritable psychiatric disorders with overlapping susceptibility loci and symptomatology. We conducted a genome-wide association study (GWAS) of these disorders in a large Swedish sample. We report a new and independent case-control analysis of 1507 SCZ cases, 836 BD cases and 2093 controls. No single-nucleotide polymorphisms (SNPs) achieved significance in these new samples; however, combining new and previously reported SCZ samples (2111 SCZ and 2535 controls) revealed a genome-wide significant association in the major histocompatibility complex (MHC) region (rs886424, P=4.54 × 10(-8)). Imputation using multiple reference panels and meta-analysis with the Psychiatric Genomics Consortium SCZ results underscored the broad, significant association in the MHC region in the full SCZ sample. We evaluated the role of copy number variants (CNVs) in these subjects. As in prior reports, deletions were enriched in SCZ, but not BD cases compared with controls. Singleton deletions were more frequent in both case groups compared with controls (SCZ: P=0.003, BD: P=0.013), whereas the largest CNVs (>500 kb) were significantly enriched only in SCZ cases (P=0.0035). Two CNVs with previously reported SCZ associations were also overrepresented in this SCZ sample: 16p11.2 duplications (P=0.0035) and 22q11 deletions (P=0.03). These results reinforce prior reports of significant MHC and CNV associations in SCZ, but not BD.

The genetic influence on diverticular disease--a twin study.

BACKGROUND: The contribution of hereditary factors to the development of diverticular disease (DD) of the colon is unknown. Prevalence and location of diverticula differ in Western world compared to in Asia and several case reports describing families with DD have been published. AIM: To assess the heritability of DD in a large population-based sample of twins. METHODS: The Swedish Twin Registry was cross-linked to the Swedish Inpatient Registry. All twins, born between 1886 and 1980 and not dead before 1969, with a discharge diagnosis of DD were identified. Twins with diagnoses of colon cancer, coeliac disease or non-infectious colitis were excluded to decrease bias. Co-twin odds ratio (OR), concordance rates and tetrachoric correlations were calculated for monozygotic (MZ) and same gender-dizygotic (SS-DZ) twins. Mx-analyses were used to estimate the relative contributions of genetic effects and environmental factors to susceptibility for DD. Calculations were based on both primary and secondary discharge diagnoses to provide estimates reflecting impact of severity of the disease. RESULTS: A total of 104,452 twins met the inclusion criteria. Of these, 2296 had a diagnosis of DD. The OR of developing the disease given one's co-twin was affected was 7.15 (95% CI: 4.82-10.61) for MZ and 3.20 (95% CI: 2.21-4.63) for SS-DZ twins. Similarly, concordance rates and tetrachoric correlations were higher in MZ than those in SS-DZ twins. The heritability was estimated to 40% and the non shared environmental effects to 60%. CONCLUSION: Genetic susceptibility is an important component, along with individual specific environmental factors, for the development of diverticular disease of the colon.

Multicenter dizygotic twin cohort study confirms two linkage susceptibility loci for body mass index at 3q29 and 7q36 and identifies three further potential novel loci.

OBJECTIVE: To identify common loci and potential genetic variants affecting body mass index (BMI, kg m(-2)) in study populations originating from Europe. DESIGN: We combined genome-wide linkage scans of six cohorts from Australia, Denmark, Finland, the Netherlands, Sweden and the United Kingdom with an approximately 10-cM microsatellite marker map. Variance components linkage analysis was carried out with age, sex and country of origin as covariates. SUBJECTS: The GenomEUtwin consortium consists of twin cohorts from eight countries (Australia, Denmark, the Netherlands, Finland, Italy, Norway, Sweden and the United Kingdom) with a total data collection of more than 500,000 monozygotic and dizygotic (DZ) twin pairs. Variance due to early-life events and the environment is reduced within twin pairs, which makes DZ pairs highly valuable for linkage studies of complex traits. This study totaled 4401 European-originated twin families (10,535 individuals) from six countries (Australia, Denmark, the Netherlands, Finland, Sweden and the United Kingdom). RESULTS: We found suggestive evidence for a quantitative trait locus on 3q29 and 7q36 in the combined sample of DZ twins (multipoint logarithm of odds score (MLOD) 2.6 and 2.4, respectively). Two individual cohorts showed strong evidence independently for three additional loci: 16q23 (MLOD=3.7) and 2p24 (MLOD=3.4) in the Dutch cohort and 20q13 (MLOD=3.2) in the Finnish cohort. CONCLUSION: Linkage analysis of the combined data in this large twin cohort study provided evidence for suggestive linkage to BMI. In addition, two cohorts independently provided significant evidence of linkage to three new loci. The results of our study suggest a smaller environmental variance between DZ twins than full siblings, with a corresponding increase in heritability for BMI as well as an increase in linkage signal in well-replicated regions. The results are consistent with the possibility of locus heterogeneity for some genomic regions, and indicate a lack of major common quantitative trait locus variants affecting BMI in European populations.

MHC loci affecting cervical cancer risk: distinguishing the effects of HLA-DQB1 and non-HLA genes TNF, LTA, TAP1 and TAP2.

Cervical cancer has been associated with specific human leukocyte antigen (HLA) haplotypes/alleles and with polymorphisms at the nearby non-HLA loci TNF, LTA, TAP1 and TAP2. Distinguishing effects of individual loci in the major histocompatibility complex (MHC) region are difficult due to the complex linkage disequilibrium (LD) pattern characterized by high LD, punctuated by recombination hot spots. We have evaluated the association of polymorphism at HLA class II DQB1 and the TNF, LTA, TAP1 and TAP2 genes with cervical cancer risk, using 1306 familial cases and 288 controls. DQB1 was strongly associated; alleles *0301, *0402 and (*)0602 increased cancer susceptibility, whereas *0501 and *0603 decreased susceptibility. Among the non-HLA loci, association was only detected for the TAP2 665 polymorphism, and interallelic disequilibrium analysis indicated that this could be due to LD with DQB1. As the TAP2 665 association was seen predominantly in non-carriers of DQB1 susceptibility alleles, we hypothesized that TAP2 665 may have an effect not attributable to LD with DQB1. However, a logistic regression analysis suggested that TAP2 665 was strongly influenced by LD with DQB1. Our results emphasize the importance of large sample sizes and underscore the necessity of examining both HLA and non-HLA loci in the MHC to assign association to the correct locus.

Low intelligence test scores in 18 year old men and risk of suicide: cohort study.

OBJECTIVE: To examine the association between intelligence test scores in men, measured at age 18, and subsequent suicide. DESIGN: Record linkage study of the Swedish military service conscription register (1968-94) with the multi-generation register, cause of death register and census data. Four tests were performed at conscription covering logic, language, spatial, and technical skills. SETTING: Sweden. PARTICIPANTS: 987 308 Swedish men followed up for 5-26 years. MAIN OUTCOME MEASURE: Suicide. RESULTS: 2811 suicides occurred during follow up. The risk of suicide was two to three times higher in those with lowest compared with the highest test scores. The strongest associations were seen with the logic test: for each unit increase in test score the risk of suicide decreased by 12% (95% confidence interval 10% to 14%). Associations were only slightly attenuated when we controlled for parents' socioeconomic position. Greatest risks were seen among poorly performing offspring of well educated parents. CONCLUSIONS: Performance in intelligence tests is strongly related to subsequent risk of suicide in men. This may be due to the importance of cognitive ability in either the aetiology of serious mental disorder or an individual's capacity to solve problems while going through an acute life crisis or suffering from mental illness.

Warfarin sensitivity related to CYP2C9, CYP3A5, ABCB1 (MDR1) and other factors.

The required dose of the oral anticoagulant warfarin varies greatly, and overdosing often leads to bleeding. Warfarin is metabolised by cytochrome P450 enzymes CYP2C9, CYP1A2 and CYP3A. The target cell level of warfarin may be dependent on the efflux pump P-glycoprotein, encoded by the adenosine triphosphate-binding cassette gene ABCB1 (multidrug resistance gene 1). Genetic variability in CYP2C9, CYP3A5 and ABCB1 was analysed in 201 stable warfarin-treated patients using solid-phase minisequencing, pyrosequencing and SNaPshot. CYP2C9 variants, age, weight, concurrent drug treatment and indication for treatment significantly influenced warfarin dosing in these patients, explaining 29% of the variation in dose. CYP3A5 did not affect warfarin dosing. An ABCB1 haplotype containing the exon 26 3435T variant was over-represented among low-dose patients. Thirty-six patients with serious bleeding complications had higher prothrombin time international normalised ratios than 189 warfarin-treated patients without serious bleeding, but there were no significant differences in CYP2C9, CYP3A5 or ABCB1 genotypes and allelic variants.

Familial resemblance of body mass index and familial risk of high and low body mass index. A study of young men in Sweden.

OBJECTIVE: Male familial correlations in body mass index (BMI) were studied using a large nationwide dataset of Swedish military conscripts examined at age 18-19 y. DESIGN: Record linkage was performed between Sweden's Military Service Conscription Register and the Multiple-Generation Register, enabling the identification of 92 869 families containing at least two brothers. Data on BMI at conscription was available for 196 743 sons and for 19 972 fathers. Pairs of relatives were used to estimate Pearson correlation coefficients for BMI, and to examine whether there are BMI intervals that show particularly strong familial resemblance. RESULTS: All biological family relations showed highly significant correlations for BMI: 0.28 (95% CI 0.27-0.29) for father-son pairs; 0.36 (0.35-0.37) for full-brothers, 0.21 (0.18-0.24) for maternal half-brothers, and 0.11 (0.08-0.14) for paternal half-brothers. Also, a significant correlation, of 0.06 (0.01-0.11), was found for non-biological quasi father-son relations. Full-brothers were more similar with respect to BMI at age 18 than father-son pairs, and maternal half-brothers were more similar than paternal half-brothers. The familial risk of having BMI values above or below various cut-offs was found to be equally strong for low BMI as for high BMI values. CONCLUSION: The almost twice as strong BMI correlation between maternal half-brothers as between paternal half-brothers illustrates the importance of factors of non-additive genetic origin, to the familial aggregation of BMI. The significant BMI association found between biologically unrelated individuals from the same family emphasizes that assortative mating (and regional clustering) should be taken into account when the heritability of BMI is estimated.