M Arfan Ikram

Erasmus Universiteit Rotterdam, Rotterdam, South Holland, Netherlands

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Publications (216)2109.33 Total impact

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    ABSTRACT: Adiposity, as indicated by body mass index (BMI), has been associated with risk of cardiovascular diseases in epidemiological studies. We aimed to investigate if these associations are causal, using Mendelian randomization (MR) methods. The associations of BMI with cardiovascular outcomes [coronary heart disease (CHD), heart failure and ischaemic stroke], and associations of a genetic score (32 BMI single nucleotide polymorphisms) with BMI and cardiovascular outcomes were examined in up to 22 193 individuals with 3062 incident cardiovascular events from nine prospective follow-up studies within the ENGAGE consortium. We used random-effects meta-analysis in an MR framework to provide causal estimates of the effect of adiposity on cardiovascular outcomes. There was a strong association between BMI and incident CHD (HR = 1.20 per SD-increase of BMI, 95% CI, 1.12-1.28, P = 1.9·10(-7)), heart failure (HR = 1.47, 95% CI, 1.35-1.60, P = 9·10(-19)) and ischaemic stroke (HR = 1.15, 95% CI, 1.06-1.24, P = 0.0008) in observational analyses. The genetic score was robustly associated with BMI (β = 0.030 SD-increase of BMI per additional allele, 95% CI, 0.028-0.033, P = 3·10(-107)). Analyses indicated a causal effect of adiposity on development of heart failure (HR = 1.93 per SD-increase of BMI, 95% CI, 1.12-3.30, P = 0.017) and ischaemic stroke (HR = 1.83, 95% CI, 1.05-3.20, P = 0.034). Additional cross-sectional analyses using both ENGAGE and CARDIoGRAMplusC4D data showed a causal effect of adiposity on CHD. Using MR methods, we provide support for the hypothesis that adiposity causes CHD, heart failure and, previously not demonstrated, ischaemic stroke. © The Author 2015; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.
    International Journal of Epidemiology 05/2015; DOI:10.1093/ije/dyv094 · 9.20 Impact Factor
  • Cerebrovascular Diseases 05/2015; 39(5-6):319-324. DOI:10.1159/000381138 · 3.70 Impact Factor
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    ABSTRACT: ADAMTS13 cleaves von Willebrand factor, reducing its prothrombotic activity. The genetic determinants of ADAMTS13 activity remain unclear. We performed a genome-wide association study of ADAMTS13 activity in the Rotterdam Study, a population-based cohort study. We used imputed genotypes of common variants in a discovery sample of 3,443 individuals and replication sample of 2,025 individuals. We examined rare exonic variant associations in ADAMTS13 in 1,609 individuals using an exome array. rs41314453 in ADAMTS13 was associated with ADAMTS13 activity in both our discovery (Beta: -20.2%, P-value: 1.3×10(-33)) and replication sample (P-value: 3.3×10(-34)), and explained 3.6-6.5% of the variance. In the combined analysis of our discovery and replication samples, there were two further independent associations at the ADAMTS13 locus: rs3118667 (Beta: 3.0, P-value: 9.6×10(-21)) and rs139911703 (Beta: -11.6, P-value: 3.6×10(-8)). Additionally, rs10456544 in SUPT3H was associated with a 4.2 increase in ADAMTS13 activity (P-value: 1.13.6×10(-8)). Finally, we found three independent associations with rare coding variants in ADAMTS13: rs148312697 (Beta: -32.2%, P-value: 3.7×10(-6)), rs142572218 (Beta: -46.0%, P-value: 3.9×10(-5)), and rs36222275 (Beta: -13.9%, P-value: 2.9×10(-3)). In conclusion, we identified rs41314453 as the main genetic determinant of ADAMTS13 activity, and present preliminary for further associations at the ADAMTS13 and SUPT3H loci. Copyright © 2015 American Society of Hematology.
    Blood 05/2015; DOI:10.1182/blood-2015-02-629865 · 9.78 Impact Factor
  • Neurology 05/2015; DOI:10.1212/WNL.0000000000001606 · 8.30 Impact Factor
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    Stroke 04/2015; DOI:10.1161/STROKEAHA.115.008222 · 6.02 Impact Factor
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    Molecular Psychiatry 04/2015; · 15.15 Impact Factor
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    ABSTRACT: To identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive functioning and information processing speed in non-demented older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. Neuropsychological testing was available for 5429-32 070 subjects of European ancestry aged 45 years or older, free of dementia and clinical stroke at the time of cognitive testing from 20 cohorts in the discovery phase. We analyzed performance on the Trail Making Test parts A and B, the Letter Digit Substitution Test (LDST), the Digit Symbol Substitution Task (DSST), semantic and phonemic fluency tests, and the Stroop Color and Word Test. Replication was sought in 1311-21860 subjects from 20 independent cohorts. A significant association was observed in the discovery cohorts for the single-nucleotide polymorphism (SNP) rs17518584 (discovery P-value=3.12 × 10(-8)) and in the joint discovery and replication meta-analysis (P-value=3.28 × 10(-9) after adjustment for age, gender and education) in an intron of the gene cell adhesion molecule 2 (CADM2) for performance on the LDST/DSST. Rs17518584 is located about 170 kb upstream of the transcription start site of the major transcript for the CADM2 gene, but is within an intron of a variant transcript that includes an alternative first exon. The variant is associated with expression of CADM2 in the cingulate cortex (P-value=4 × 10(-4)). The protein encoded by CADM2 is involved in glutamate signaling (P-value=7.22 × 10(-15)), gamma-aminobutyric acid (GABA) transport (P-value=1.36 × 10(-11)) and neuron cell-cell adhesion (P-value=1.48 × 10(-13)). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed.Molecular Psychiatry advance online publication, 14 April 2015; doi:10.1038/mp.2015.37.
    Molecular Psychiatry 04/2015; DOI:10.1038/mp.2015.37 · 15.15 Impact Factor
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    ABSTRACT: -Epidemiological findings suggest a relationship between Alzheimer's disease (AD), inflammation and dyslipidemia, although the nature of this relationship is not well understood. We investigated whether this phenotypic association arises from a shared genetic basis. -Using summary statistics (p-values and odds ratios) from genome-wide association studies of over 200,000 individuals, we investigated overlap in single nucleotide polymorphisms (SNPs) associated with clinically diagnosed AD and C-reactive protein (CRP), triglycerides (TG), high- (HDL) and low-density lipoprotein (LDL) levels. We found up to 50-fold enrichment of AD SNPs for different levels of association with CRP, LDL, HDL and TG SNPs using an FDR threshold < 0.05. By conditioning on polymorphisms associated with the four phenotypes, we identified 55 loci associated with increased AD risk. We then conducted a meta-analysis of these 55 variants across four independent AD cohorts (total n = 29,054 AD cases and 114,824 healthy controls) and discovered two genome-wide significant variants on chromosome 4 (rs13113697, closest gene HS3ST1, odds ratio (OR) = 1.07, 95% confidence interval (CI) = 1.05-1.11, p = 2.86 x 10(-8)) and chromosome 10 (rs7920721, closest gene ECHDC3, OR = 1.07, 95% CI = 1.04-1.11, p = 3.38 x 10(-8)). We also found that gene expression of HS3ST1 and ECHDC3 was altered in AD brains compared with control brains. -We demonstrate genetic overlap between AD, CRP, and plasma lipids. By conditioning on the genetic association with the cardiovascular phenotypes, we identify novel AD susceptibility loci including two genome-wide significant variants conferring increased risk for Alzheimer's disease.
    Circulation 04/2015; DOI:10.1161/CIRCULATIONAHA.115.015489 · 14.95 Impact Factor
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    ABSTRACT: To determine the risk of stroke associated with subclinical hypothyroidism. Data Sources and Study Selection Published prospective cohort studies were identified through a systematic search through November 2013 without restrictions in several databases. Unpublished studies were identified through the Thyroid Studies Collaboration. We collected individual participant data (IPD) on thyroid function and stroke outcome. Euthyroidism was defined as thyrotropin (TSH) levels 0.45-4.49 mIU/L, subclinical hypothyroidism as TSH levels 4.5-19.9 mIU/L with normal thyroxin levels. Data Extraction and Synthesis We collected IPD on 47,573 adults (3451 subclinical hypothyroidism) from 17 cohorts, followed-up 1972-2014 (489,192 person-years). Age- and sex-adjusted pooled hazard ratio (HR) for participants with subclinical hypothyroidism compared to euthyroidism was 1.05 (95% CI, 0.91-1.21) for stroke events (combined fatal and non-fatal stroke) and 1.07 (95% CI, 0.80-1.42) for fatal stroke. Stratified by age, the HR for stroke events was 3.32 (95% CI, 1.25-8.80) for individuals aged 18-49 years. There was an increased risk of fatal stroke in the age groups 18-49 and 50-64 years with a HR of 4.22 (95% CI, 1.08-16.55) and 2.86 (95% CI, 1.31-6.26), respectively (p trend 0.04). We found no increased risk for those 65-79 years (HR 1.00, 95% CI, 0.86-1.18) or ≥80 years (HR 1.31, 95% CI, 0.79-2.18). There was a pattern of increased risk of fatal stroke with higher TSH concentrations. Although no overall effect of subclinical hypothyroidism on stroke could be demonstrated, an increased risk in subjects younger than 65 years and those with higher TSH concentrations was observed.
    The Journal of Clinical Endocrinology and Metabolism 04/2015; DOI:10.1210/jc.2015-1438 · 6.31 Impact Factor
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    ABSTRACT: Cognitive functioning changes with age, sleep and the circadian rhythm. We investigated whether these factors are independently associated with different cognitive domains assessed in middle-aged and elderly persons.
    Sleep Medicine 04/2015; DOI:10.1016/j.sleep.2015.03.012 · 3.10 Impact Factor
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    ABSTRACT: Background Anatomic and hemodynamic similarities between renal and cerebral vessels suggest a tight link between kidney disease and brain disease. Although several distinct markers are used to identify subclinical kidney and brain disease, a comprehensive assessment of how these markers link damage at both end organs is lacking.AimTo investigate whether measures of kidney function were associated with cerebral small vessel disease on MRI.Methods In 2526 participants of the population-based Rotterdam Study, we measured urinary albumin-to-creatinine ratio, and estimated glomerular filtration rate based on serum creatinine and cystatin C. All participants underwent brain magnetic resonance imaging. We assessed presence of cerebral small vessel disease by calculating white matter lesion volumes and rating the presence of lacunes and cerebral microbleeds. We used multivariable linear and logistic regression to investigate the association between kidney function and cerebral small vessel disease.ResultsWorse kidney function was consistently associated with a larger white matter lesion volume (mean difference per standard deviation increase in albumin-to-creatinine ratio: 0·09, 95% confidence interval 0·05; 0·12; per standard deviation decrease in creatinine-based estimated glomerular filtration rate: −0·04, 95% confidence interval −0·08;−0·01, and per standard deviation decrease in cystatin C-based estimated glomerular filtration rate: −0·09, 95% confidence interval −0·13;−0·05). Persons with higher albumin-to-creatinine ratio or lower cystatin C-based estimated glomerular filtration rate levels had a higher prevalence of lacunes (odds ratio per standard deviation increase in albumin-to-creatinine ratio: 1·24, 95% confidence interval 1·07; 1·43). Only participants in the highest quartile of albumin-to-creatinine ratio had a higher frequency of microbleeds compared to the lowest quartile.Conclusions Worse kidney function is associated with cerebral small vessel disease. Of all measures of kidney function, in particular albumin-to-creatinine ratio is related to cerebral small vessel disease.
    International Journal of Stroke 04/2015; DOI:10.1111/ijs.12465 · 4.03 Impact Factor
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    ABSTRACT: APOE ɛ4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE ɛ4+ (10 352 cases and 9207 controls) and APOE ɛ4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ɛ4 status. Suggestive associations (P<1 × 10(-4)) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ɛ4+: 1250 cases and 536 controls; APOE ɛ4-: 718 cases and 1699 controls). Among APOE ɛ4- subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 data sets (best SNP, rs2732703, P=5·8 × 10(-9)). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100-kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ɛ4+ subjects (CR1 and CLU) or APOE ɛ4- subjects (MS4A6A/MS4A4A/MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6 × 10(-7)) is noteworthy, because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P⩽1.3 × 10(-8)), frontal cortex (P⩽1.3 × 10(-9)) and temporal cortex (P⩽1.2 × 10(-11)). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2 × 10(-6)) and temporal cortex (P=2.6 × 10(-6)). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ɛ4 compared with persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted.Molecular Psychiatry advance online publication, 17 March 2015; doi:10.1038/mp.2015.23.
    Molecular Psychiatry 03/2015; DOI:10.1038/mp.2015.23 · 15.15 Impact Factor
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    ABSTRACT: Adjuvant chemotherapy for breast cancer has been associated with deterioration of fine motor skill. Which aspects of motor performance are underlying this problem is unclear but important because manual motor deterioration could affect quality of life. The current study aims to investigate late effects of adjuvant chemotherapy for breast cancer on fine motor function, using both speed and accuracy measures. We compared fine motor function of 174 women who had received adjuvant Cyclophosphamide Methotrexate 5-Fluorouracil chemotherapy for breast cancer on average 20 years ago with that of a population sample of 195 women without a history of cancer. Fine motor function was measured with the Purdue Pegboard Test and the Archimedes spiral test. The group of chemotherapy-exposed breast cancer survivors was slower in drawing an Archimedes spiral than the reference group. Furthermore, in the chemotherapy-exposed subjects, we found that older age is related to more crossings of the spiral template, more return movements, and more deviations from the template. Such relationships were not observed within the reference group. No significant between-group differences were found for any of the Purdue Pegboard measures. Compared with a population-based reference group, Cyclophosphamide Methotrexate 5-Fluorouracil chemotherapy-exposed breast cancer survivors demonstrated motor slowing while drawing an Archimedes spiral, on average 20 years after completion of primary treatment. Furthermore, the Archimedes spiral test is a more sensitive measure than the Purdue Pegboard Test to assess fine manual motor performance in long-term breast cancer survivors following chemotherapy. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.
    Psycho-Oncology 03/2015; DOI:10.1002/pon.3796 · 4.04 Impact Factor
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    ABSTRACT: Introduction: The cognitive reserve hypothesis suggests that across the lifespan, higher education, regular participation in social or mentally stimulating activities, and complexity of occupation increase an individual's resistance to dementia. However, there is currently no consensus regarding how to assess or measure cognitive reserve. Method: We performed a systematic review of reviews focused on the concept of cognitive reserve to examine key elements of the definition and highlight limitations. We searched Embase.com, MEDLINE (OvidSP), the Cochrane Library, Web of Science, Scopus, Google Scholar, and PubMed. Results: Five systematic reviews were identified. These incorporated findings from cohort, cross-sectional, and case-control studies, and the outcomes examined included Alzheimer's disease, vascular dementia, nonspecified dementia, all dementias, and cognitive decline or cognitive impairment. Education, occupation, and leisure or mentally stimulating activities were suggested to supply cognitive reserve and offer a protective effect against the risk of dementia. Premorbid IQ and socioeconomic status have not been investigated as thoroughly and showed inconsistent results. Two of the reviews showed that when combining different indicators in the analyses/definition, including education, occupation, mentally stimulating activities, and premorbid IQ, cognitive reserve had a protective effect against cognitive decline. However, other indicators may also supply the reserve, including dietary habits and genetic indicators, but research is lacking with regard to creating a full cognitive reserve model. Conclusions: This review highlights the lack of consensus regarding a definition of cognitive reserve. Further research is required to clarify how the indicators already identified may provide cognitive reserve and offer a protective effect against dementia. Agreement on the indicators that constitute the cognitive reserve model is needed before testing possible interventions that may increase the reserve supply and improve cognition.
    Journal of Clinical and Experimental Neuropsychology 03/2015; DOI:10.1080/13803395.2014.1002759 · 2.16 Impact Factor
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    ABSTRACT: Objective: To test whether mutations in gamma-aminobutyric acid type A receptor (GABAA-R) subunit genes contribute to the etiology of Rolandic epilepsy (RE) or its atypical variants (ARE). Methods: We performed exome sequencing to compare the frequency of variants in 18 GABAA-R genes in 204 European patients with RE/ARE versus 728 platform matched controls. Identified GABRG2 variants were functionally assessed for protein stability, trafficking, postsynaptic clustering and receptor function. Results: Out of 18 screened GABAA-R genes, we detected an enrichment of rare variants in the GABRG2 gene in RE/ARE patients (5/204, 2.45%) in comparison to controls (1/723, 0.14%) (OR = 18.07, 95% CI = 2.01 – 855.07, p = 0.0024, pcorr = 0.043). We identified a GABRG2 splice variant (c.549-3T>G) in two unrelated patients as well as three nonsynonymous variations in this gene (p.G257R, p.R323Q, p.I389V). Functional assessment showed reduced surface expression of p.G257R and decreased GABA-evoked currents for p.R323Q. The p.G257R mutation displayed diminished levels of palmitoylation, a posttranslational modification crucial for trafficking of proteins to the cell membrane. Enzymatically raised palmitoylation levels restored the surface expression of the p.G257R variant γ2-subunit. Interpretation: The statistical association and the functional evidence suggest that mutations of the GABRG2 gene may increase the risk of RE/ARE. Restoring the impaired membrane trafficking of some GABRG2 mutations by enhancing palmitoylation might be an interesting therapeutic approach to reverse the pathogenic effect of such mutants. This article is protected by copyright. All rights reserved.
    Annals of Neurology 02/2015; DOI:10.1002/ana.24395 · 11.91 Impact Factor
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    ABSTRACT: Observational studies have reported different effects of adiposity on cardiovascular risk factors across age and sex. Since cardiovascular risk factors are enriched in obese individuals, it has not been easy to dissect the effects of adiposity from those of other risk factors. We used a Mendelian randomization approach, applying a set of 32 genetic markers to estimate the causal effect of adiposity on blood pressure, glycemic indices, circulating lipid levels, and markers of inflammation and liver disease in up to 67,553 individuals. All analyses were stratified by age (cutoff 55 years of age) and sex. The genetic score was associated with BMI in both nonstratified analysis (P = 2.8 × 10(-107)) and stratified analyses (all P < 3.3 × 10(-30)). We found evidence of a causal effect of adiposity on blood pressure, and fasting levels of insulin, C-reactive protein, interleukin-6, HDL cholesterol, and triglycerides in a nonstratified analysis and in the <55-year stratum. Further, we found evidence of a smaller causal effect on total cholesterol (P for difference = 0.015) in the ≥55-year stratum than in the <55-year stratum, a finding that could be explained by biology, survival bias, or differential medication. In conclusion, this study extends previous knowledge of the effects of adiposity by providing sex- and age-specific causal estimates on cardiovascular risk factors. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
    Diabetes 02/2015; DOI:10.2337/db14-0988 · 8.47 Impact Factor
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    ABSTRACT: Gait disturbances in patients with chronic obstructive pulmonary disease (COPD) may lead to disability and falls. As studies assessing gait kinematics in COPD are sparse, we investigated associations of COPD with various gait domains and explored a potential link with falling. Gait was measured within the prospective, population-based Rotterdam Study (age ⩾55 years) using an electronic walkway and summarised into seven gait domains: Rhythm, Variability, Phases, Pace, Tandem, Turning and Base of Support. Rhythm is a temporal gait aspect that includes cadence and reflects how quickly steps are taken. Persons with COPD (n=196) exhibited worse Rhythm (-0.21 sd, 95% CI -0.36- -0.06 sd) compared with persons with normal lung function (n=898), independent of age, sex, height, education, smoking or analgesic use, especially when dyspnoea and severe airflow limitation or frequent exacerbations (Global Initiative for Chronic Obstructive Lung Disease group D: -0.83 sd, 95% CI -1.25- -0.41 sd) were present. A lower forced expiratory volume in 1 s was associated with worse Rhythm and Pace, including lower cadence and gait velocity, respectively. Importantly, fallers with COPD had significantly worse Rhythm than nonfallers with COPD. This study demonstrates that persons with COPD exhibit worse Rhythm, especially fallers with COPD. The degree of Rhythm deterioration was associated with the degree of airflow limitation, symptoms and frequency of exacerbations. Copyright ©ERS 2015.
    European Respiratory Journal 02/2015; DOI:10.1183/09031936.00213214 · 7.13 Impact Factor
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    ABSTRACT: We investigated the genetic overlap between Alzheimer's disease (AD) and Parkinson's disease (PD). Using summary statistics (P-values) from large recent genome-wide association studies (GWAS) (total n=89 904 individuals), we sought to identify single nucleotide polymorphisms (SNPs) associating with both AD and PD. We found and replicated association of both AD and PD with the A allele of rs393152 within the extended MAPT region on chromosome 17 (meta analysis P-value across five independent AD cohorts=1.65 × 10(-7)). In independent datasets, we found a dose-dependent effect of the A allele of rs393152 on intra-cerebral MAPT transcript levels and volume loss within the entorhinal cortex and hippocampus. Our findings identify the tau-associated MAPT locus as a site of genetic overlap between AD and PD, and extending prior work, we show that the MAPT region increases risk of Alzheimer's neurodegeneration.Molecular Psychiatry advance online publication, 17 February 2015; doi:10.1038/mp.2015.6.
    Molecular Psychiatry 02/2015; DOI:10.1038/mp.2015.6 · 15.15 Impact Factor
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    ABSTRACT: Introduction The relationship between positive psychological well-being (PPWB) and cardiovascular disease (CVD) is inconsistent across different CVD outcomes and for different PPWB constructs, such as positive affect. In addition, the relationship between PPWB and CVD as a composite measure is rarely assessed. Objective To assess whether positive affect is protective of incident CVD. Method Positive affect was assessed in two cohorts between 1993 and 2001 in Rotterdam using relevant questions from the Center for Epidemiological Studies Depression (CES-D) scale and the Hospital Anxiety and Depression Scale (HADS; in a sub-sample) in 6,349 non-demented, CVD-free, consenting adults, aged 55 + years. Composite CVD was defined as stroke, heart failure and coronary heart disease, which were continuously monitored through medical records until 1st April 2010. Results There were 1,480 (23.3%) first time CVD events during follow-up (11.9 + 2.8SD years, 58,416 person-years). Positive affect was not associated with incident CVD (CES-D HR: 1.00 per point, 95%CI: 0.98-1.02; HADS HR: 0.98, 95%CI: 0.92-1.05). Stratification by age or sex and assessment of separate CVD outcome did not change results. Conclusion In this large, population-based study, there was no association between positive affect and twelve-year incident CVD in older adults who were free of diagnosed CVD at baseline.
    Preventive Medicine 02/2015; 74. DOI:10.1016/j.ypmed.2015.01.032 · 2.93 Impact Factor
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    ABSTRACT: -The burden of cerebral white matter hyperintensities (WMH) is associated with an increased risk of stroke, dementia, and death. WMH are highly heritable, but their genetic underpinnings are incompletely characterized. To identify novel genetic variants influencing WMH burden, we conducted a meta-analysis of multi-ethnic genome-wide association studies. -We included 21,079 middle-aged to elderly individuals from 29 population-based cohorts, who were free of dementia and stroke and were of European (N=17,936), African (N=1,943), Hispanic (N=795), and Asian (N=405) descent. WMH burden was quantified on MRI either by a validated automated segmentation method or a validated visual grading scale. Genotype data in each study were imputed to the 1000 Genomes reference. Within each ethnic group, we investigated the relationship between each SNP and WMH burden using a linear regression model adjusted for age, sex, intracranial volume, and principal components of ancestry. A meta-analysis was conducted for each ethnicity separately and for the combined sample. In the European descent samples, we confirmed a previously known locus on chr17q25 (p=2.7×10(-19)) and identified novel loci on chr10q24 (p=1.6×10(-9)) and chr2p21 (p=4.4×10(-8)). In the multi-ethnic meta-analysis, we identified two additional loci, on chr1q22 (p=2.0×10(-8)) and chr2p16 (p=1.5×10(-8)). The novel loci contained genes that have been implicated in Alzheimer's disease (chr2p21, chr10q24), intracerebral hemorrhage (chr1q22), neuro-inflammatory diseases (chr2p21), and glioma (chr10q24, chr2p16). -We identified four novel genetic loci that implicate inflammatory and glial proliferative pathways in the development of white matter hyperintensities in addition to previously-proposed ischemic mechanisms.
    Circulation Cardiovascular Genetics 02/2015; DOI:10.1161/CIRCGENETICS.114.000858 · 5.34 Impact Factor

Publication Stats

5k Citations
2,109.33 Total Impact Points

Institutions

  • 2009–2015
    • Erasmus Universiteit Rotterdam
      • Department of Epidemiology
      Rotterdam, South Holland, Netherlands
  • 2006–2015
    • Erasmus MC
      • • Department of Neurology
      • • Department of Epidemiology
      Rotterdam, South Holland, Netherlands
  • 2012
    • St George's, University of London
      • Stroke and Dementia Research Centre
      Londinium, England, United Kingdom
  • 2010
    • University of Massachusetts Boston
      Boston, Massachusetts, United States
  • 2008
    • Leiden University Medical Centre
      Leyden, South Holland, Netherlands