A genome-wide scan for common variants affecting the rate of age-related cognitive decline

Institute for the Neurosciences, Department of Neurology, Brigham and Women's Hospital, Boston, MA 02115, USA.
Neurobiology of aging (Impact Factor: 5.01). 11/2011; 33(5):1017.e1-15. DOI: 10.1016/j.neurobiolaging.2011.09.033
Source: PubMed


Age-related cognitive decline is likely promoted by accumulated brain injury due to chronic conditions of aging, including neurodegenerative and vascular disease. Because common neuronal mechanisms may mediate the adaptation to diverse cerebral insults, we hypothesized that susceptibility for age-related cognitive decline may be due in part to a shared genetic network. We have therefore performed a genome-wide association study using a quantitative measure of global cognitive decline slope, based on repeated measures of 17 cognitive tests in 749 subjects from the Religious Orders Study. Top results were evaluated in 3 independent replication cohorts, consisting of 2279 additional subjects with repeated cognitive testing. As expected, we find that the Alzheimer's disease (AD) susceptibility locus, APOE, is strongly associated with rate of cognitive decline (P(DISC) = 5.6 × 10(-9); P(JOINT)= 3.7 × 10(-27)). We additionally discover a variant, rs10808746, which shows consistent effects in the replication cohorts and modestly improved evidence of association in the joint analysis (P(DISC) = 6.7 × 10(-5); P(REP) = 9.4 × 10(-3); P(JOINT) = 2.3 × 10(-5)). This variant influences the expression of 2 adjacent genes, PDE7A and MTFR1, which are potential regulators of inflammation and oxidative injury, respectively. Using aggregate measures of genetic risk, we find that known susceptibility loci for cardiovascular disease, type 2 diabetes, and inflammatory diseases are not significantly associated with cognitive decline in our cohort. Our results suggest that intermediate phenotypes, when coupled with larger sample sizes, may be a useful tool to dissect susceptibility loci for age-related cognitive decline and uncover shared molecular pathways with a role in neuronal injury.

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    • "Although the current study identified concurrent effects of type of CSLA and APOE genotype, few longitudinal effects were found. This result appears contrary to some genetic research identifying the APOE ɛ4 as a key allelic variation that influences normal age-related cognitive decline (De Jager et al., 2012; Niti et al., 2008) or the development of AD or dementia (Ferrari et al., 2013). For example, Niti et al. (2008) found that participating in at least one physical, social or productive activity (e.g., reading) significantly reduced the risk of cognitive decline for non-ɛ4 carriers, whereas this protective relationship was only seen for productive activities in ɛ4-carriers. "
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    ABSTRACT: The current study examined independent and interactive effects between Apolipoprotein E (APOE) genotype and two types of cognitively-stimulating lifestyle activities (CSLA)-integrated information processing (CSLA-II) and novel information processing (CSLA-NI)-on concurrent and longitudinal changes in cognition. Three-wave data across 6 years of follow-up from the Victoria Longitudinal Study (n=278; ages 55-94) and linear mixed model analyses were used to characterize the effects of APOE genotype and participation in CSLA-II and CSLA-NI in four cognitive domains. Significant CSLA effects on cognition were observed. More frequent participation in challenging activities (i.e., CSLA-NI) was associated with higher baseline scores on word recall, fact recall, vocabulary and verbal fluency. Conversely, higher participation in less cognitively-challenging activities (i.e., CSLA-II) was associated with lower scores on fact recall and verbal fluency. No longitudinal CSLA-cognition effects were found. Two significant genetic effects were observed. First, APOE moderated CSLA-II and CSLA-NI associations with baseline verbal fluency and fact recall scores. Second, APOE non-ɛ4 carriers' baseline performance were more likely to be moderated by CSLA participation, compared to APOE-ɛ4 carriers. Our findings suggest APOE may be a "plasticity" gene that makes individuals more or less amenable to the influence of protective factors such as CSLA. (JINS, 2014, 20, 1-9).
    Full-text · Article · May 2014 · Journal of the International Neuropsychological Society
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    • "Similarly, few GWA signals have emerged for general cognitive abilities in either children or adults (e.g., Benyamin et al. 2013, Davies et al. 2011, Docherty et al. 2010) or, aside from APOE, for cognitive decline with aging (e.g., De Jager et al. 2012). Finally, a few GWA studies have examined major personality traits (e.g., de Moor et al. 2012, Service et al. 2012, Terracciano et al. 2010, van den Oord et al. 2008, Verweij et al. 2010), but again show only sporadic associations. "
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    ABSTRACT: With the advent of increasingly accessible technologies for typing genetic variation, studies of gene-environment (G×E) interactions have proliferated in psychological research. Among the aims of such studies are testing developmental hypotheses and models of the etiology of behavioral disorders, defining boundaries of genetic and environmental influences, and identifying individuals most susceptible to risk exposures or most amenable to preventive and therapeutic interventions. This research also coincides with the emergence of unanticipated difficulties in detecting genetic variants of direct association with behavioral traits and disorders, which may be obscured if genetic effects are expressed only in predisposing environments. In this essay we consider these and other rationales for positing G×E interactions, review conceptual models meant to inform G×E interpretations from a psychological perspective, discuss points of common critique to which G×E research is vulnerable, and address the role of the environment in G×E interactions.
    Full-text · Article · Jan 2014 · Annual Review of Psychology
    • "Variants in GSTO2 (glutathione S-transferase omega-2), which codes for a subunit of glutathione transferase, have also been associated with decreased levels of glutathione which increase levels of ROS as well as AD susceptibility [98]. Two other genes related to oxidative stress have been identified in large studies of AD-related endophenotypes, including the associations of MTFR1 (mitochondrial fission regulator 1) with cognitive decline [99] and MSRB3 (methionine sulfoxide reductase B3) with hippocampal volume [56]. "
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    ABSTRACT: The discovery of causative genetic mutations in affected family members has historically dominated our understanding of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS). Nevertheless, most cases of neurodegenerative disease are not explained by Mendelian inheritance of known genetic variants, but instead are thought to have a complex etiology with numerous genetic and environmental factors contributing to susceptibility. Although unbiased genome-wide association studies (GWAS) have identified novel associations to neurodegenerative diseases, most of these hits explain only modest fractions of disease heritability. In addition, despite the substantial overlap of clinical and pathologic features among major neurodegenerative diseases, surprisingly few GWAS-implicated variants appear to exhibit cross-disease association. These realities suggest limitations of the focus on individual genetic variants and create challenges for the development of diagnostic and therapeutic strategies, which traditionally target an isolated molecule or mechanistic step. Recently, GWAS of complex diseases and traits have focused less on individual susceptibility variants and instead have emphasized the biological pathways and networks revealed by genetic associations. This new paradigm draws on the hypothesis that fundamental disease processes may be influenced on a personalized basis by a combination of variants - some common and others rare, some protective and others deleterious - in key genes and pathways. Here, we review and synthesize the major pathways implicated in neurodegeneration, focusing on GWAS from the most prevalent neurodegenerative disorders, AD and PD. Using literature mining, we also discover a novel regulatory network that is enriched with AD- and PD-associated genes and centered on the SP1 and AP-1 (Jun/Fos) transcription factors. Overall, this pathway- and network-driven model highlights several potential shared mechanisms in AD and PD that will inform future studies of these and other neurodegenerative disorders. These insights also suggest that biomarker and treatment strategies may require simultaneous targeting of multiple components, including some specific to disease stage, in order to assess and modulate neurodegeneration. Pathways and networks will provide ideal vehicles for integrating relevant findings from GWAS and other modalities to enhance clinical translation.
    No preview · Article · Oct 2013 · American Journal of Neurodegenerative Diseases
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