Abstract
Although genome-wide association studies (GWAS) have proven remarkably effective at identifying reliably associated genetic variants, the biology underlying these discoveries is rarely immediately apparent and in most cases seems bound to require extensive fine mapping and functional analysis before it is revealed. In this context, it is logical and appropriate to try to interrogate available genetic data for biological insights. However, because such efforts invariably depend upon mathematical modeling, misperceptions can easily arise if the relevant mathematical properties are overlooked or forgotten. In this report, we will examine these mathematical issues, highlight some of the more common misconceptions, and hopefully help to clarify the somewhat blurry distinction between biology and mathematics that can so easily undermine and obscure the value of GWAS discoveries. Ann Neurol 2012;
Abstract
Objective:
A study was undertaken to relate dietary fat types to cognitive change in healthy community-based elders.
Methods:
Among 6,183 older participants in the Women's Health Study, we related intake of major fatty acids (saturated [SFA], monounsaturated [MUFA], total polyunsaturated [PUFA], trans-unsaturated) to late-life cognitive trajectory. Serial cognitive testing, conducted over 4 years, began 5 years after dietary assessment. Primary outcomes were global cognition (averaging tests of general cognition, verbal memory, and semantic fluency) and verbal memory (averaging tests of recall). We used analyses of response profiles and logistic regression to estimate multivariate-adjusted differences in cognitive trajectory and risk of worst cognitive change (worst 10%) by fat intake.
Results:
Higher SFA intake was associated with worse global cognitive (p for linear trend = 0.008) and verbal memory (p for linear trend = 0.01) trajectories. There was a higher risk of worst cognitive change, comparing highest versus lowest SFA quintiles; the multivariate-adjusted odds ratio (OR) with 95% confidence interval (CI) was 1.64 (1.04–2.58) for global cognition and 1.65 (1.04–2.61) for verbal memory. By contrast, higher MUFA intake was related to better global cognitive (p for linear trend < 0.001) and verbal memory (p for linear trend = 0.009) trajectories, and lower OR (95% CI) of worst cognitive change in global cognition (0.52 [0.31–0.88]) and verbal memory (0.56 [0.34–0.94]). Total fat, PUFA, and trans-fat intakes were not associated with cognitive trajectory.
Interpretation:
Higher SFA intake was associated with worse global cognitive and verbal memory trajectories, whereas higher MUFA intake was related to better trajectories. Thus, different consumption levels of the major specific fat types, rather than total fat intake itself, appeared to influence cognitive aging. ANN NEUROL 2012;
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Medscape Medical News
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Medscape Business of Medicine
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Medscape Medical News
Abstract
Objective: Large genome-wide association studies (GWAS) have identified many novel genes influencing Alzheimer disease (AD) risk, but most of the genetic variance remains une×plained. We conducted a two-stage GWAS for AD-related quantitative measures of hippocampal volume (HV), total cerebral volume (TCV), and white matter hyperintensities (WMH).
Methods: Brain MRI measures of HV, TCV and WMH were obtained from 981 Caucasian and 419 African American AD cases and their cognitively normal siblings in the MIRAGE Study, and from 168 AD cases, 336 individuals with mild cognitive impairment and 188 controls in the ADNI Study. A GWAS for each trait was conducted in the two Caucasian datasets in stage 1. Results from the two datasets were combined by meta analysis. In stage 2, one SNP from each region that was nominally significant in each dataset (p<0.05) and strongly associated in both datasets (p<1.0×10-5) was evaluated in the African American dataset.
Results: Twenty-two markers (14 for HV, 3 for TCV, and 5 for WMH) from distinct regions met criteria for evaluation in stage 2. Novel genome-wide significant associations (p<5.0×10-8) were attained for HV with SNPs in the APOE, F5/SELP, LHFP and GCFC2 gene regions. All of these associations were supported by evidence in each dataset. Associations with different SNPs in the same gene (p<1×10-5 in Caucasians and p<2.2×10-4 in African Americans) were also observed for PICALM with HV, SYNPR with TCV and TTC27 with WMH.
Interpretation: Our study demonstrates the efficacy of endophenotypes for broadening our understanding of the genetic basis of AD. ANN NEUROL 2012