Common variants at 12q14 and 12q24 are associated with hippocampal volume

Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA.
Nature Genetics (Impact Factor: 29.35). 04/2012; 44(5):545-51. DOI: 10.1038/ng.2237
Source: PubMed


Aging is associated with reductions in hippocampal volume that are accelerated by Alzheimer's disease and vascular risk factors. Our genome-wide association study (GWAS) of dementia-free persons (n = 9,232) identified 46 SNPs at four loci with P values of <4.0 × 10(-7). In two additional samples (n = 2,318), associations were replicated at 12q14 within MSRB3-WIF1 (discovery and replication; rs17178006; P = 5.3 × 10(-11)) and at 12q24 near HRK-FBXW8 (rs7294919; P = 2.9 × 10(-11)). Remaining associations included one SNP at 2q24 within DPP4 (rs6741949; P = 2.9 × 10(-7)) and nine SNPs at 9p33 within ASTN2 (rs7852872; P = 1.0 × 10(-7)); along with the chromosome 12 associations, these loci were also associated with hippocampal volume (P < 0.05) in a third younger, more heterogeneous sample (n = 7,794). The SNP in ASTN2 also showed suggestive association with decline in cognition in a largely independent sample (n = 1,563). These associations implicate genes related to apoptosis (HRK), development (WIF1), oxidative stress (MSR3B), ubiquitination (FBXW8) and neuronal migration (ASTN2), as well as enzymes targeted by new diabetes medications (DPP4), indicating new genetic influences on hippocampal size and possibly the risk of cognitive decline and dementia.

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    • "ASTN2 is expressed at high levels in migrating cerebellar granule neurons at developmental stages when glial-guided migration occurs (Wilson et al., 2010). SNPs in this gene have been associated with schizophrenia and metabolic side effects of antipsychotic drugs, as well as with autism, attention deficit hyperactivity disorder, hippocampal volume, and cognition (Lesch et al., 2008; Vrijenhoek et al., 2008; Glessner et al., 2009; Wang et al., 2010; Adkins et al., 2011; Lionel et al., 2011; Bis et al., 2012). DCDC2 gene is located on chromosome 6p22.1, "
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    • "The goal of the effort was to bring together researchers with genome-wide data and images, to meta-analyze evidence in neuroimaging datasets worldwide (see Fig. 2). In Stein et al. (2012), the ENIGMA consortium, in collaboration with another multi-site consortium (CHARGE; Seshadri et al. 2010; Fornage et al. 2011; Bis et al. 2012; Ikram et al. 2012) reported that the mean bilateral volume of the hippocampus was significantly associated with the intergenic variant rs7294919 (see Forest plots, Fig. 3). "
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