Ida K. Karlsson

Exploring the Causal Pathway from Telomere Length to Coronary Heart Disease: A Network Mendelian Randomization Study

Rationale: Observational studies have found shorter leukocyte telomere length (TL) to be a risk factor for coronary heart disease (CHD), and recently the association was suggested to be causal. However, the relationship between TL and common metabolic risk factors for CHD is not well understood. Whether these risk factors could explain pathways from TL to CHD warrants further attention. Objective: To examine whether metabolic risk factors for CHD mediate the causal pathway from short TL to increased risk of CHD using a network Mendelian randomization design. Methods and Results: Summary statistics from several genome-wide association studies were used in a 2-sample Mendelian randomization study design. Network Mendelian randomization analysis—an approach using genetic variants as the instrumental variables for both the exposure and mediator to infer causality—was performed to examine the causal association between telomeres and CHD and metabolic risk factors. Summary statistics from the ENGAGE Telomere Consortium were used (n=37 684) as a TL genetic instrument, CARDIoGRAMplusC4D Consortium data were used (case=22 233 and control=64 762) for CHD, and other consortia data were used for metabolic traits (fasting insulin, triglyceride, total cholesterol, low-density lipoprotein cholesterol, fasting glucose, diabetes mellitus, glycohemoglobin, body mass index, waist circumference, and waist:hip ratio). One-unit increase of genetically determined TL was associated with −0.07 (95% confidence interval, −0.01 to −0.12; P=0.01) lower log-transformed fasting insulin (pmol/L) and 21% lower odds (95% confidence interval, 3–35; P=0.02) of CHD. Higher genetically determined log-transformed fasting insulin level was associated with higher CHD risk (odds ratio, 1.86; 95% confidence interval, 1.01–3.41; P=0.04). Conclusions: Overall, our findings support a role of insulin as a mediator on the causal pathway from shorter telomeres to CHD pathogenesis.

Apolipoprotein E ε4 genotype and the temporal relationship between depression and dementia

To investigate how apolipoprotein E (APOE) affects the temporal relationship between depression and dementia, we conducted a nested case-control study with longitudinal depression and dementia evaluations from several population studies by using 804 dementia cases and 1600 matched controls, totaling 1519 unique individuals. Depression within 10 years of onset of dementia was strongly associated with dementia diagnosis regardless of APOE status (incidence rate ratio [IRR] 5.25, 95% confidence interval [95% CI] 3.32-8.31 for ε4 carriers, IRR 4.40, 95%CI 3.23-5.99 for noncarriers). However, we found a significant interaction between depression more than 10 years before the onset of dementia and APOE (p = 0.01), with depression more distal to dementia being a risk factor only in ε4 carriers (IRR 3.39, 95% CI 1.69-6.78 for carriers, IRR 1.01, 95% CI 0.60-1.70 for noncarriers). Thus, depression with onset close in time to dementia onset is associated with disease irrespective of APOE genotype, whereas depression more distal to dementia onset is a risk factor only in ε4-carriers. This is the first study to show the interaction between APOE and depression to be dependent on timing of depression onset.

Genetic meta-analysis identifies 10 novel loci and functional pathways for Alzheimer's disease risk

Late onset Alzheimer’s disease (AD) is the most common form of dementia with more than 35 million people affected worldwide, and no curative treatment available. AD is highly heritable and recent genome-wide meta-analyses have identified over 20 genomic loci associated with AD, yet only explaining a small proportion of the genetic variance indicating that undiscovered loci exist. Here, we performed the largest genome-wide association study of clinically diagnosed AD and AD-by-proxy (71,880 AD cases, 383,378 controls). AD-by-proxy status is based on parental AD diagnosis, and showed strong genetic correlation with AD (rg=0.81). Genetic meta analysis identified 29 risk loci, of which 9 are novel, and implicating 215 potential causative genes. Independent replication further supports these novel loci in AD. Associated genes are strongly expressed in immune-related tissues and cell types (spleen, liver and microglia). Furthermore, gene-set analyses indicate the genetic contribution of biological mechanisms involved in lipid-related processes and degradation of amyloid precursor proteins. We show strong genetic correlations with multiple health-related outcomes, and Mendelian randomisation results suggest a protective effect of cognitive ability on AD risk. These results are a step forward in identifying more of the genetic factors that contribute to AD risk and add novel insights into the neurobiology of AD to guide new drug development.

Detection of Dementia Cases in Two Swedish Health Registers: A Validation Study

Background: Population-based health registers are potential assets in epidemiological research; however, the quality of case ascertainment is crucial. Objective: To compare the case ascertainment of dementia, from the National Patient Register (NPR) and the Cause of Death Register (CDR) with dementia diagnoses from six Swedish population based studies. Methods: Sensitivity, specificity, and positive predictive value (PPV) of dementia identification in NPR and CDR were estimated by individual record linkage with six Swedish population based studies (n = 19,035). Time to detection in NPR was estimated using data on dementia incidence from longitudinal studies with more than two decades of follow-up. Results: Barely half of the dementia cases were ever detected by NPR or CDR. Using data from longitudinal studies we estimated that a record with a dementia diagnosis appears in the NPR on average 5.5 years after first diagnosis. Although the ability of the registers to detect dementia cases was moderate, the ability to detect non-dementia cases was almost perfect (99%). When registers indicate that there is a dementia diagnosis, there are very few instances in which the clinicians determined the person was not demented. Indeed, PPVs were close to 90%. However, misclassification between dementia subtype diagnoses is quite common, especially in NPR. Conclusions: Although the overall sensitivity is low, the specificity and the positive predictive value are very high. This suggests that hospital and death registers can be used to identify dementia cases in the community, but at the cost of missing a large proportion of the cases.

Dementia: Genes, Environments, Interactions

Dementia is an increasingly prevalent disorder as the world population ages, with Alzheimer disease the most common cause. Twin studies find concordance to be substantially higher among monozygotic as compared with dizygotic twin pairs. While a few genes have been identified that are responsible for early-onset Alzheimer disease, they account for well under 5 % of all cases. Among susceptibility genes for Alzheimer disease identified by association studies, population attributable fraction for the most prominent of these—apolipoprotein E—is estimated to be about 25 %, whereas other genes at best predict another 20 %. There are few strong environmental risk or protective factors, with vascular risks the best established, although with mechanisms still not fully understood. It seems likely that clusters of risk alleles, interactions between risk alleles and environmental exposures, and epigenetic mechanisms play a role in explaining Alzheimer disease, with different combinations of influences culminating in the observed pathophysiology. In particular, environmental exposures early in life could lead to deleterious changes in gene expression in late life.

Apolipoprotein E DNA methylation and late-life disease

Abstract Background This study aims to investigate if DNA methylation of the apolipoprotein E (APOE) locus affects the risks of dementia, Alzheimeŕs disease (AD) or cardiovascular disease (CVD). Methods DNA methylation across theAPOE gene has previously been categorized into three distinct regions: a hypermethylated region in the promoter, a hypomethylated region in the first two introns and exons and a hypermethylated region in the 3′exon that also harbours theAPOE ε2 and ε4 alleles. DNA methylation levels in leukocytes were measured using the Illumina 450K array in 447 Swedish twins (mean age 78.1 years). We used logistic regression to investigate whether methylation levels in those regions affect the odds of disease. Results We found that methylation levels in the promoter region were associated with dementia and AD after adjusting for sex, age at blood draw, education, smoking and relatedness among twins [odds ratio (OR) 1.32 per standard deviation increase in methylation levels, 95% confidence interval (CI) 1.08–1.62 for dementia; OR 1.38, 95% CI 1.07–1.78 for AD). We did not detect any difference in methylation levels between CVD cases and controls. Results were similar when comparing within discordant twin pairs, and did not differ as a function ofAPOE genotype. Conclusions We found that higher DNA methylation levels in the promoter region ofAPOE increase the odds of dementia and AD, but not CVD. The effect was independent ofAPOE genotype, indicating that allelic variation and methylation variation inAPOE may act independently to increase the risk of dementia.

Circulating insulin-like growth factors and Alzheimer disease: A mendelian randomization study

Objective To examine whether genetically predicted variation in circulating insulin-like growth factor 1 (IGF1) or its binding protein, IGFBP3, are associated with risk of Alzheimer disease (AD), using a mendelian randomization study design. Methods We first examined disease risk by genotypes of 9 insulin-like growth factor (IGF)–related single nucleotide polymorphisms (SNPs) using published summary genome-wide association statistics from the International Genomics of Alzheimers Project (IGAP; n = 17,008 cases; 37,154 controls). We then assessed whether any SNP-disease results replicated in an independent sample derived from the Swedish Twin Registry (n = 984 cases; 10,304 controls). Results Meta-analyses of SNP-AD results did not suggest that variation in IGF1, IGFBP3, or the molar ratio of these affect AD risk. Only one SNP appeared to affect AD risk in IGAP data. This variant is located in the gene FOXO3, implicated in human longevity. In a meta-analysis of both IGAP and secondary data, the odds ratio of AD per FOXO3 risk allele was 1.04 (95% confidence interval 1.01–1.08; p = 0.008). Conclusions These findings suggest that circulating IGF1 and IGFBP3 are not important determinants of AD risk. FOXO3 function may influence AD development via pathways that are independent of IGF signaling (i.e., pleiotropic actions).

Is the matched extreme case–control design more powerful than the nested case–control design?

For time-to-event data, the study sample is commonly selected using the nested case–control design in which controls are selected at the event time of each case. An alternative sampling strategy is to sample all controls at the same (pre-specified) time, which can either be at the last event time or further out in time. Such controls are the long-term survivors and may therefore constitute a more ‘extreme’ comparison group and be more informative than controls from the nested case–control design. We investigate this potential information gain by comparing the power of various ‘extreme’ case–control designs with that of the nested case–control design using simulation studies. We derive an expression for the theoretical average information in a nested and extreme case–control pair for the situation of a single binary exposure. Comparisons reveal that the efficiency of the extreme case–control design increases when the controls are sampled further out in time. In an application to a study of dementia, we identified Apolipoprotein E as a risk factor using a 1:1 extreme case–control design, which provided a hazard ratio estimate with a smaller standard error than that of a 2:1 nested case–control design.

Frailty index as a predictor of all-cause and cause-specific mortality in a Swedish population-based cohort

Frailty is a complex manifestation of aging and associated with increased risk of mortality and poor health outcomes. However, younger individuals (under 65 years) are less-studied in this respect. Also, the relationship between frailty and cause-specific mortality in community settings is understudied. We used a 42-item Rockwood-based frailty index (FI) in the Swedish Adoption/Twin Study of Aging (n=1477; 623 men, 854 women; aged 29-95 years) and analyzed its association with all-cause and cause-specific mortality in up to 30-years of follow-up. Deaths due to cardiovascular disease (CVD), cancer, dementia and other causes were considered as competing risks. The FI was independently associated with increased risk for all-cause mortality in younger (<65 years; HR per increase in one deficit 1.11, 95%CI 1.07-1.17) and older (≥65 years; HR 1.07, 95%CI 1.04-1.10) women and in younger men (HR 1.05, 95%CI 1.01-1.10). In cause-specific mortality analysis, the FI was strongly predictive of CVD mortality in women (HR per increase in one deficit 1.13, 95%CI 1.09-1.17), whereas in men the risk was restricted to deaths from other causes (HR 1.07, 95%CI 1.01-1.13). In conclusion, the FI is a strong mortality predictor especially among younger individuals and its associations with cause-specific mortality are sex-specific.

Genetic susceptibility to cardiovascular disease and risk of dementia

Several studies have shown cardiovascular disease (CVD) to be associated with dementia, but it is not clear whether CVD per se increases the risk of dementia or whether the association is due to shared risk factors. We tested how a genetic risk score (GRS) for coronary artery disease (CAD) affects dementia risk after CVD in 13 231 Swedish twins. We also utilized summarized genome-wide association data to study genetic overlap between CAD and Alzheimer´s disease (AD), and additionally between shared risk factors and each disease. There was no direct effect of a CAD GRS on dementia (hazard ratio 0.99, 95% confidence interval (CI): 0.98–1.01). However, the GRS for CAD modified the association between CVD and dementia within 3 years of CVD diagnosis, ranging from a hazard ratio of 1.59 (95% CI: 1.05–2.41) in the first GRS quartile to 1.91 (95% CI: 1.28–2.86) in the fourth GRS quartile. Using summary statistics, we found no genetic overlap between CAD and AD. We did, however, find that both AD and CAD share a significant genetic overlap with lipids, but that the overlap arose from clearly distinct gene clusters. In conclusion, genetic susceptibility to CAD was found to modify the association between CVD and dementia, most likely through associations with shared risk factors.