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Publications (10 of 23) Show all publications
Karlsson, I. K., Ericsson, M., Wang, Y., Jylhävä, J., Hägg, S., Pedersen, N. L., . . . Dahl Aslan, A. K. (2019). DNA methylation and body mass index during late-life - a longitudinal twin study. In: : . Paper presented at International Association of Gerontology and Geriatrics European Region Congress 2019, 23rd – 25th May 2019, Gothenburg, Sweden.
Open this publication in new window or tab >>DNA methylation and body mass index during late-life - a longitudinal twin study
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2019 (English)Conference paper, Poster (with or without abstract) (Refereed)
National Category
Gerontology, specialising in Medical and Health Sciences
Identifiers
urn:nbn:se:hj:diva-43780 (URN)
Conference
International Association of Gerontology and Geriatrics European Region Congress 2019, 23rd – 25th May 2019, Gothenburg, Sweden
Available from: 2019-05-27 Created: 2019-05-27 Last updated: 2019-05-27Bibliographically approved
Kodesh, A., Sandin, S., Reichenberg, A., Rotstein, A., Pedersen, N. L., Ericsson, M., . . . Levine, S. Z. (2019). Exposure to antidepressant medication and the risk of incident dementia. The American journal of geriatric psychiatry
Open this publication in new window or tab >>Exposure to antidepressant medication and the risk of incident dementia
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2019 (English)In: The American journal of geriatric psychiatry, ISSN 1064-7481, E-ISSN 1545-7214Article in journal (Refereed) Epub ahead of print
Abstract [en]

Objective: To test competing hypotheses that monotherapeutic antidepressant exposure is associated with an increased versus a decreased risk of dementia.

Methods: A prospective national matched cohort study from Israel (N = 71,515) without dementia (2002–2012) aged 60 and over were followed up for incident dementia from May 2013 to October 2017. Exposure to antidepressant monotherapy was classified with Anatomical Therapeutic Chemical Codes (N06A) from January 1, 2013 to December 31, 2016. The association between antidepressant monotherapy and the risk of incident dementia was quantified with hazard ratios (HR) and their 95% confidence intervals (CI) obtained from Cox regression models unadjusted and adjusted for 42 covariates. The robustness of the results was tested with 24 sensitivity analyses: 19 analyses restricted to subsamples with plausible differential dementia risks (e.g., anxiety and depression), and 5 analyses across and within antidepressant drug classes.

Results: In the primary analysis, the risk of incident dementia for the group exposed to antidepressant monotherapy compared to the group unexposed to antidepressants was estimated with an unadjusted HR = 4.09 (df = 1, 95% Wald CI = 3.64, 4.60) and an adjusted HR = 3.43 (df = 1, 95% Wald CI = 3.04, 3.88). Across the 24 sensitivity analyses the estimated adjusted HR values ranged from 1.99 to 5.47.

Conclusion: In this study, monotherapeutic antidepressant exposure in old age was associated with increased incident dementia. Clinicians, caregivers, and patients may wish to consider this potentially negative consequence of antidepressant exposure and aim to balance the costs and benefits of treatment. 

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
antidepressant medication, Dementia, depression, epidemiology
National Category
Gerontology, specialising in Medical and Health Sciences
Identifiers
urn:nbn:se:hj:diva-45327 (URN)10.1016/j.jagp.2019.05.019 (DOI)2-s2.0-85067435646 (Scopus ID);HHJARNIS (Local ID);HHJARNIS (Archive number);HHJARNIS (OAI)
Available from: 2019-07-11 Created: 2019-07-11 Last updated: 2019-07-11
Jansen, I. E., Savage, J. E., Watanabe, K., Bryois, J., Williams, D. M., Steinberg, S., . . . Posthuma, D. (2019). Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk. Nature Genetics, 51(3), 404-413
Open this publication in new window or tab >>Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk
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2019 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 51, no 3, p. 404-413Article in journal (Refereed) Published
Abstract [en]

Alzheimer’s disease (AD) is highly heritable and recent studies have identified over 20 disease-associated genomic loci. Yet these only explain a small proportion of the genetic variance, indicating that undiscovered loci remain. Here, we performed a large genome-wide association study of clinically diagnosed AD and AD-by-proxy (71,880 cases, 383,378 controls). AD-by-proxy, based on parental diagnoses, showed strong genetic correlation with AD (rg = 0.81). Meta-analysis identified 29 risk loci, implicating 215 potential causative genes. Associated genes are strongly expressed in immune-related tissues and cell types (spleen, liver, and microglia). Gene-set analyses indicate 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 randomization results suggest a protective effect of cognitive ability on AD risk. These results are a step forward in identifying the genetic factors that contribute to AD risk and add novel insights into the neurobiology of AD. 

Place, publisher, year, edition, pages
Nature Publishing Group, 2019
National Category
Neurology
Identifiers
urn:nbn:se:hj:diva-43026 (URN)10.1038/s41588-018-0311-9 (DOI)000459947200010 ()30617256 (PubMedID)2-s2.0-85059641255 (Scopus ID);HHJARNIS (Local ID);HHJARNIS (Archive number);HHJARNIS (OAI)
Available from: 2019-02-18 Created: 2019-02-18 Last updated: 2019-03-14
Karlsson, I. K., Reynolds, C. A., Escott-Price, V., Hardy, J., Gatz, M. & Pedersen, N. L. (2019). Heritability of Alzheimer's disease – Comparison of twin and polygenic methods. European Neuropsychopharmacology, 29(Suppl. 4), S1208-S1209
Open this publication in new window or tab >>Heritability of Alzheimer's disease – Comparison of twin and polygenic methods
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2019 (English)In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 29, no Suppl. 4, p. S1208-S1209Article in journal, Meeting abstract (Refereed) Published
Place, publisher, year, edition, pages
Elsevier, 2019
National Category
Neurology
Identifiers
urn:nbn:se:hj:diva-45568 (URN)10.1016/j.euroneuro.2018.08.259 (DOI)000477708400341 ()
Available from: 2019-08-15 Created: 2019-08-15 Last updated: 2019-08-15Bibliographically approved
Li, X., Ploner, A., Karlsson, I. K., Liu, X., Magnusson, P. K., Pedersen, N. L., . . . Jylhävä, J. (2019). The frailty index is a predictor of cause-specific mortality independent of familial effects from midlife onwards: a large cohort study. BMC Medicine, 17(1), Article ID 94.
Open this publication in new window or tab >>The frailty index is a predictor of cause-specific mortality independent of familial effects from midlife onwards: a large cohort study
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2019 (English)In: BMC Medicine, ISSN 1741-7015, E-ISSN 1741-7015, Vol. 17, no 1, article id 94Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Frailty index (FI) is a well-established predictor of all-cause mortality, but less is known for cause-specific mortality and whether familial effects influence the associations. Middle-aged individuals are also understudied for the association between FI and mortality. Furthermore, the population mortality impact of frailty remains understudied.

METHODS: We estimated the predictive value of FI for all-cause and cause-specific mortality, taking into account familial factors, and tested whether the associations are time-dependent. We also assessed the proportion of all-cause and cause-specific deaths that are attributable to increased levels of frailty. We analyzed 42,953 participants from the Screening Across the Lifespan Twin Study (aged 41-95 years at baseline) with up to 20 years' mortality follow-up. The FI was constructed using 44 health-related items. Deaths due to cardiovascular disease (CVD), respiratory-related causes, and cancer were considered in the cause-specific analysis. Generalized survival models were used in the analysis.

RESULTS: Increased FI was associated with higher risks of all-cause, CVD, and respiratory-related mortality, with the corresponding hazard ratios of 1.28 (1.24, 1.32), 1.31 (1.23, 1.40), and 1.23 (1.11, 1.38) associated with a 10% increase in FI in male single responders, and 1.21 (1.18, 1.25), 1.27 (1.15, 1.34), and 1.26 (1.15, 1.39) in female single responders. No significant associations were observed for cancer mortality. No attenuation of the mortality associations in unrelated individuals was observed when adjusting for familial effects in twin pairs. The associations were time-dependent with relatively greater effects observed in younger ages. Before the age of 80, the proportions of deaths attributable to FI levels > 0.21 were 18.4% of all-cause deaths, 25.4% of CVD deaths, and 20.4% of respiratory-related deaths in men and 19.2% of all-cause deaths, 27.8% of CVD deaths, and 28.5% of respiratory-related deaths in women. After the age of 80, the attributable proportions decreased, most notably for all-cause and CVD mortality.

CONCLUSIONS: Increased FI predicts higher risks of all-cause, CVD, and respiratory-related mortality independent of familial effects. Increased FI presents a relatively greater risk factor at midlife than in old age. Increased FI has a significant population mortality impact that is greatest through midlife until the age of 80.

Place, publisher, year, edition, pages
BioMed Central, 2019
Keywords
Attributable fraction, Familial effect, Frailty index, Mortality, Time-varying effect
National Category
Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:hj:diva-43973 (URN)10.1186/s12916-019-1331-8 (DOI)000468058000001 ()31088449 (PubMedID)2-s2.0-85065730346 (Scopus ID)GOA HHJ 2019 (Local ID)GOA HHJ 2019 (Archive number)GOA HHJ 2019 (OAI)
Available from: 2019-06-03 Created: 2019-06-03 Last updated: 2019-06-03Bibliographically approved
Karlsson, I. K., Ploner, A., Wang, Y., Gatz, M., Pedersen, N. L. & Hagg, S. (2018). Apolipoprotein E DNA methylation and late-life disease. International Journal of Epidemiology, 47(3), 899-907
Open this publication in new window or tab >>Apolipoprotein E DNA methylation and late-life disease
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2018 (English)In: International Journal of Epidemiology, ISSN 0300-5771, E-ISSN 1464-3685, Vol. 47, no 3, p. 899-907Article in journal (Refereed) Published
Abstract [en]

Background: This study aims to investigate if DNA methylation of the apolipoprotein E (APOE) locus affects the risks of dementia, Alzheimers disease (AD) or cardiovascular disease (CVD).

Methods: DNA methylation across the APOE 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 the APOE epsilon 2 and epsilon 4 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 of APOE genotype.

Conclusions: We found that higher DNA methylation levels in the promoter region of APOE increase the odds of dementia and AD, but not CVD. The effect was independent of APOE genotype, indicating that allelic variation and methylation variation in APOE may act independently to increase the risk of dementia.

Place, publisher, year, edition, pages
Oxford University Press, 2018
Keywords
Epigenetics, methylation, apolipoprotein E, dementia, Alzheimers disease, cardiovascular disease, ageing
National Category
Neurology
Identifiers
urn:nbn:se:hj:diva-41592 (URN)10.1093/ije/dyy025 (DOI)000438342200026 ()29509901 (PubMedID)
Available from: 2018-09-26 Created: 2018-09-26 Last updated: 2018-09-26Bibliographically approved
Williams, D. M., Karlsson, I. K., Pedersen, N. L. & Hägg, S. (2018). Circulating insulin-like growth factors and Alzheimer disease: A mendelian randomization study. Neurology, 90(4), e291-e297
Open this publication in new window or tab >>Circulating insulin-like growth factors and Alzheimer disease: A mendelian randomization study
2018 (English)In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 90, no 4, p. e291-e297Article in journal (Refereed) Published
Abstract [en]

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 Alzheimer's 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).

Place, publisher, year, edition, pages
Wolters Kluwer, 2018
National Category
Neurology
Identifiers
urn:nbn:se:hj:diva-41591 (URN)10.1212/WNL.0000000000004854 (DOI)000427799500004 ()29282328 (PubMedID)
Available from: 2018-09-26 Created: 2018-09-26 Last updated: 2018-09-26Bibliographically approved
Rizzuto, D., Feldman, A. L., Karlsson, I. K., Dahl Aslan, A. K., Gatz, M. & Pedersen, N. L. (2018). Detection of dementia cases in two Swedish health registers: A validation study. Journal of Alzheimer's Disease, 61(4), 1301-1310
Open this publication in new window or tab >>Detection of dementia cases in two Swedish health registers: A validation study
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2018 (English)In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 61, no 4, p. 1301-1310Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
IOS Press, 2018
Keywords
Alzheimer’s disease, dementia, population-based registers, validation study, vascular dementia
National Category
Neurology Geriatrics
Identifiers
urn:nbn:se:hj:diva-38884 (URN)10.3233/JAD-170572 (DOI)000423364400006 ()29376854 (PubMedID)2-s2.0-85048059412 (Scopus ID)HHJARNIS (Local ID)HHJARNIS (Archive number)HHJARNIS (OAI)
Available from: 2018-02-20 Created: 2018-02-20 Last updated: 2019-03-22Bibliographically approved
Karlsson, I. K., Hallgren, J., Pedersen, N. L., Reynolds, C. A. & Dahl Aslan, A. K. (2018). Genetic influences on body mass index across Adulthood and late-life. Paper presented at The Gerontological Society of America's 70th Annual Scientific Meeting, Boston, November 14-18, 2018. Innovation in Aging, 2(suppl_1), 620-620
Open this publication in new window or tab >>Genetic influences on body mass index across Adulthood and late-life
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2018 (English)In: Innovation in Aging, ISSN 1556-343X, Vol. 2, no suppl_1, p. 620-620Article in journal, Meeting abstract (Refereed) Published
Abstract [en]

Although genetic factors significantly contribute to variation in body-mass index (BMI), the effects appear to differ with age. To investigate this, we applied polygenic methods to longitudinal data from the Swedish Twin Registry where BMI was available for age categories ranging from 20–35 to above 80. Using GCTA, a polygenic method to estimate heritability, we showed that heritability explains around 20% of the variability in BMI across age categories. However, a polygenic risk score based on the largest GWAS of BMI (PRSBMI) explained 4–6% of the variation in BMI before 65, but less than 0.5% after age 65. This indicates that while there is substantial heritability of BMI across adulthood and late-life, the genetic variants identified in GWAS mainly predict BMI before age 65. Hence, more work is warranted studying the genetics of BMI in late-life, to better understand its biology and what distinguishes it from BMI earlier in adulthood.

Place, publisher, year, edition, pages
Oxford University Press, 2018
National Category
Gerontology, specialising in Medical and Health Sciences
Identifiers
urn:nbn:se:hj:diva-42749 (URN)10.1093/geroni/igy023.2311 (DOI)HHJARNIS (Local ID)HHJARNIS (Archive number)HHJARNIS (OAI)
Conference
The Gerontological Society of America's 70th Annual Scientific Meeting, Boston, November 14-18, 2018
Available from: 2019-01-24 Created: 2019-01-24 Last updated: 2019-01-24Bibliographically approved
Savage, J. E., Jansen, P. R., Stringer, S., Watanabe, K., Bryois, J., De Leeuw, C. A., . . . Posthuma, D. (2018). Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence. Nature Genetics, 50(7), 912-919
Open this publication in new window or tab >>Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence
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2018 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 50, no 7, p. 912-919Article in journal (Refereed) Published
Abstract [en]

Intelligence is highly heritable 1 and a major determinant of human health and well-being 2 . Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence 3-7, but much about its genetic underpinnings remains to be discovered. Here, we present a large-scale genetic association study of intelligence (n = 269,867), identifying 205 associated genomic loci (190 new) and 1,016 genes (939 new) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and associations with 146 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain, specifically in striatal medium spiny neurons and hippocampal pyramidal neurons. Gene set analyses implicate pathways related to nervous system development and synaptic structure. We confirm previous strong genetic correlations with multiple health-related outcomes, and Mendelian randomization analysis results suggest protective effects of intelligence for Alzheimer's disease and ADHD and bidirectional causation with pleiotropic effects for schizophrenia. These results are a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders.

Place, publisher, year, edition, pages
Nature Publishing Group, 2018
Keywords
Alzheimer disease, Article, attention deficit disorder, chromatin, conserved sequence, corpus striatum, exon, expression quantitative trait locus, gene expression, gene location, gene locus, gene mapping, genetic association, genetic correlation, genetic variability, genome-wide association study, heredity, hippocampus, human, intelligence, medium spiny neuron, Mendelian randomization analysis, nervous system development, pleiotropy, priority journal, pyramidal nerve cell, schizophrenia, synapse
National Category
Neurology
Identifiers
urn:nbn:se:hj:diva-41590 (URN)10.1038/s41588-018-0152-6 (DOI)000437224400005 ()29942086 (PubMedID)2-s2.0-85048943479 (Scopus ID)
Available from: 2018-09-26 Created: 2018-09-26 Last updated: 2018-09-26Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-3605-7829

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