Patrik K. E. Magnusson

Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts

Recent genome-wide association (GWA) studies of lipids have been conducted in samples ascertained for other phenotypes, particularly diabetes. Here we report the first GWA analysis of loci affecting total cholesterol (TC), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglycerides sampled randomly from 16 population-based cohorts and genotyped using mainly the Illumina HumanHap300-Duo platform. Our study included a total of 17,797–22,562 persons, aged 18–104 years and from geographic regions spanning from the Nordic countries to Southern Europe. We established 22 loci associated with serum lipid levels at a genome-wide significance level (P < 5 × 10−8), including 16 loci that were identified by previous GWA studies. The six newly identified loci in our cohort samples are ABCG5 (TC, P = 1.5 × 10−11; LDL, P = 2.6 × 10−10), TMEM57 (TC, P = 5.4 × 10−10), CTCF-PRMT8 region (HDL, P = 8.3 × 10−16), DNAH11 (LDL, P = 6.1 × 10−9), FADS3-FADS2 (TC, P = 1.5 × 10−10; LDL, P = 4.4 × 10−13) and MADD-FOLH1 region (HDL, P = 6 × 10−11). For three loci, effect sizes differed significantly by sex. Genetic risk scores based on lipid loci explain up to 4.8% of variation in lipids and were also associated with increased intima media thickness (P = 0.001) and coronary heart disease incidence (P = 0.04). The genetic risk score improves the screening of high-risk groups of dyslipidemia over classical risk factors.

A polygenic burden of rare disruptive mutations in schizophrenia

Schizophrenia is a common disease with a complex aetiology, probably involving multiple and heterogeneous genetic factors. Here, by analysing the exome sequences of 2,536 schizophrenia cases and 2,543 controls, we demonstrate a polygenic burden primarily arising from rare (less than 1 in 10,000), disruptive mutations distributed across many genes. Particularly enriched gene sets include the voltage-gated calcium ion channel and the signalling complex formed by the activity-regulated cytoskeleton-associated scaffold protein (ARC) of the postsynaptic density, sets previously implicated by genome-wide association and copy-number variation studies. Similar to reports in autism, targets of the fragile X mental retardation protein (FMRP, product of FMR1) are enriched for case mutations. No individual gene-based test achieves significance after correction for multiple testing and we do not detect any alleles of moderately low frequency (approximately 0.5 to 1 per cent) and moderately large effect. Taken together, these data suggest that population-based exome sequencing can discover risk alleles and complements established gene-mapping paradigms in neuropsychiatric disease.

Consistent high viral load of human papillomavirus 16 and risk of cervical carcinoma in situ: a nested case-control study

BACKGROUND Persistent infection with certain types of human papillomavirus (HPV) is believed to be a prerequisite for the development of cervical neoplasia. Persistence may depend on certain characteristics, such as viral load, which has so far been given little attention. We investigated the association between HPV 16 viral load and cervical carcinoma in situ. METHODS We did a nested case-control study of women participating in cytological screening in Sweden. We used a sensitive quantitative PCR assay to estimate HPV 16 load in multiple smears for each woman, taken during a period of up to 26 years before diagnosis. We calculated C, values, which decrease as the number of viral DNA copies increases. FINDINGS 2081 smears from 478 cases and 1754 smears from 608 controls were tested. Among cases, we found a consistently increased load of HPV 16 already 13 years or more before diagnosis, and when many smears were still cytologically normal. Women with high HPV 16 viral loads were at least 30 times the relative risk of HPV-16-negative women more than a decade before diagnosis. The increase in relative risk was constant over time. About 25% of women (95% CI 0.12-0.32) infected with a high viral load before age 25 years developed cervical carcinoma in situ within 15 years. INTERPRETATION Cervical carcinoma in situ associated with HPV 16 occurs mainly in HPV-16-positive women who have consistently high viral loads long term. Women at high risk could be identified by use of a quantitative HPV test in addition to cytological screening.

Exome sequencing and the genetic basis of complex traits

Shamil Sunyaev and colleagues present exome sequencing methods and their applications in studies to identify the genetic basis of human complex traits. They include analyses of the whole-exome sequences of 438 individuals from across several studies.

A Genomewide Screen of 345 Families for Autism-Susceptibility Loci

We previously reported a genomewide scan to identify autism-susceptibility loci in 110 multiplex families, showing suggestive evidence (P <.01) for linkage to autism-spectrum disorders (ASD) on chromosomes 5, 8, 16, 19, and X and showing nominal evidence (P <.05) on several additional chromosomes (2, 3, 4, 10, 11, 12, 15, 18, and 20). In this follow-up analysis we have increased the sample size threefold, while holding the study design constant, so that we now report 345 multiplex families, each with at least two siblings affected with autism or ASD phenotype. Along with 235 new multiplex families, 73 new microsatellite markers were also added in 10 regions, thereby increasing the marker density at these strategic locations from 10 cM to approximately 2 cM and bringing the total number of markers to 408 over the entire genome. Multipoint maximum LOD scores (MLS) obtained from affected-sib-pair analysis of all 345 families yielded suggestive evidence for linkage on chromosomes 17, 5, 11, 4, and 8 (listed in order by MLS) (P <.01). The most significant findings were an MLS of 2.83 (P =.00029) on chromosome 17q, near the serotonin transporter (5-hydroxytryptamine transporter [5-HTT]), and an MLS of 2.54 (P =.00059) on 5p. The present follow-up genome scan, which used a consistent research design across studies and examined the largest ASD sample collection reported to date, gave either equivalent or marginally increased evidence for linkage at several chromosomal regions implicated in our previous scan but eliminated evidence for linkage at other regions.

Genetic variance estimation with imputed variants finds negligible missing heritability for human height and body mass index

We propose a method (GREML-LDMS) to estimate heritability for human complex traits in unrelated individuals using whole-genome sequencing data. We demonstrate using simulations based on whole-genome sequencing data that ∼97% and ∼68% of variation at common and rare variants, respectively, can be captured by imputation. Using the GREML-LDMS method, we estimate from 44,126 unrelated individuals that all ∼17 million imputed variants explain 56% (standard error (s.e.) = 2.3%) of variance for height and 27% (s.e. = 2.5%) of variance for body mass index (BMI), and we find evidence that height- and BMI-associated variants have been under natural selection. Considering the imperfect tagging of imputation and potential overestimation of heritability from previous family-based studies, heritability is likely to be 60–70% for height and 30–40% for BMI. Therefore, the missing heritability is small for both traits. For further discovery of genes associated with complex traits, a study design with SNP arrays followed by imputation is more cost-effective than whole-genome sequencing at current prices.

Long term exposure to ambient air pollution and incidence of acute coronary events: prospective cohort study and meta-analysis in 11 European cohorts from the ESCAPE Project

Objectives To study the effect of long term exposure to airborne pollutants on the incidence of acute coronary events in 11 cohorts participating in the European Study of Cohorts for Air Pollution Effects (ESCAPE). Design Prospective cohort studies and meta-analysis of the results. Setting Cohorts in Finland, Sweden, Denmark, Germany, and Italy. Participants 100 166 people were enrolled from 1997 to 2007 and followed for an average of 11.5 years. Participants were free from previous coronary events at baseline. Main outcome measures Modelled concentrations of particulate matter <2.5 μm (PM2.5), 2.5-10 μm (PMcoarse), and <10 μm (PM10) in aerodynamic diameter, soot (PM2.5 absorbance), nitrogen oxides, and traffic exposure at the home address based on measurements of air pollution conducted in 2008-12. Cohort specific hazard ratios for incidence of acute coronary events (myocardial infarction and unstable angina) per fixed increments of the pollutants with adjustment for sociodemographic and lifestyle risk factors, and pooled random effects meta-analytic hazard ratios. Results 5157 participants experienced incident events. A 5 μg/m3 increase in estimated annual mean PM2.5 was associated with a 13% increased risk of coronary events (hazard ratio 1.13, 95% confidence interval 0.98 to 1.30), and a 10 μg/m3 increase in estimated annual mean PM10 was associated with a 12% increased risk of coronary events (1.12, 1.01 to 1.25) with no evidence of heterogeneity between cohorts. Positive associations were detected below the current annual European limit value of 25 μg/m3 for PM2.5 (1.18, 1.01 to 1.39, for 5 μg/m3 increase in PM2.5) and below 40 μg/m3 for PM10 (1.12, 1.00 to 1.27, for 10 μg/m3 increase in PM10). Positive but non-significant associations were found with other pollutants. Conclusions Long term exposure to particulate matter is associated with incidence of coronary events, and this association persists at levels of exposure below the current European limit values.

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

ABSTRACTThe 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.

Most Reported Genetic Associations With General Intelligence Are Probably False Positives

General intelligence (g) and virtually all other behavioral traits are heritable. Associations between g and specific single-nucleotide polymorphisms (SNPs) in several candidate genes involved in brain function have been reported. We sought to replicate published associations between g and 12 specific genetic variants (in the genes DTNBP1, CTSD, DRD2, ANKK1, CHRM2, SSADH, COMT, BDNF, CHRNA4, DISC1, APOE, and SNAP25) using data sets from three independent, well-characterized longitudinal studies with samples of 5,571, 1,759, and 2,441 individuals. Of 32 independent tests across all three data sets, only 1 was nominally significant. By contrast, power analyses showed that we should have expected 10 to 15 significant associations, given reasonable assumptions for genotype effect sizes. For positive controls, we confirmed accepted genetic associations for Alzheimer’s disease and body mass index, and we used SNP-based calculations of genetic relatedness to replicate previous estimates that about half of the variance in g is accounted for by common genetic variation among individuals. We conclude that the molecular genetics of psychology and social science requires approaches that go beyond the examination of candidate genes.

Genetic link to cervical tumours.

Cervical cancer is strongly associated with infection by oncogenic types of human papilloma virus (HPV). But only a small fraction of those infected develop cancer, indicating that other factors contribute to the progression to cervical cancer. We have compared incidence of the disease in relatives of cases of cervical tumour and controls, and find a significant familial clustering among biological, but not adoptive, relatives. We find no difference in the risk to siblings who have a mother or father in common, so the clustering cannot be explained by vertical transmission of HPV from mother to child. These results provide epidemiological evidence of a genetic predisposition to cervical cancer.