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Shulman, Joshua M.

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Shulman

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Joshua M.

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Shulman, Joshua M.
Author's Publications: search.filters.isAuthorOfPublication.9e680862-3abb-41ca-929d-ddaad8a44e1a

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    Common variants at 12q14 and 12q24 are associated with hippocampal volume
    (2012) Bis, Joshua C.; DeCarli, Charles; Smith, Albert Vernon; van der Lijn, Fedde; Crivello, Fabrice; Fornage, Myriam; Debette, Stephanie; Shulman, Joshua M.; Schmidt, Helena; Srikanth, Velandai; Schuur, Maaike; Yu, Lei; Choi, Seung-Hoan; Sigurdsson, Sigurdur; Verhaaren, Benjamin F.J.; DeStefano, Anita L.; Lambert, Jean-Charles; Jack, Clifford R.; Struchalin, Maksim; Stankovich, Jim; Ibrahim-Verbaas, Carla A.; Fleischman, Debra; Zijdenbos, Alex; den Heijer, Tom; Mazoyer, Bernard; Coker, Laura H.; Enzinger, Christian; Danoy, Patrick; Amin, Najaf; Arfanakis, Konstantinos; van Buchem, Mark A.; de Bruijn, Renée F.A.G.; Beiser, Alexa; Dufouil, Carole; Huang, Juebin; Cavalieri, Margherita; Thomson, Russell; Niessen, Wiro J.; Chibnik, Lori; Gislason, Gauti K.; Hofman, Albert; Pikula, Aleksandra; Amouyel, Philippe; Freeman, Kevin B.; Phan, Thanh G.; Oostra, Ben A.; Stein, Jason L.; Medland, Sarah E.; Vasquez, Alejandro Arias; Hibar, Derrek P.; Wright, Margaret J.; Franke, Barbara; Martin, Nicholas G.; Thompson, Paul M.; Nalls, Michael A.; Uitterlinden, Andre G.; Au, Rhoda; Elbaz, Alexis; Beare, Richard J.; van Swieten, John C.; Lopez, Oscar; Harris, Tamara B.; Chouraki, Vincent; Breteler, Monique; De Jager, Philip; Becker, James T.; Vernooij, Meike W.; Knopman, David; Fazekas, Franz; Wolf, Philip A.; van der Lugt, Aad; Gudnason, Vilmundur; Longstreth, W.T.; Brown, Mathew A.; Bennett, David A.; van Duijn, Cornelia M.; Mosley, Thomas H.; Schmidt, Reinhold; Tzourio, Christophe; Launer, Lenore J.; Ikram, M. Arfan; Seshadri, Sudha
    Aging is associated with reductions in hippocampal volume (HV) that are accelerated by Alzheimer’s disease and vascular risk factors. Our genome-wide association study of dementia-free persons (n=9,232) identified 46 SNPs at four loci with p-values <4.0×10-7. Two additional samples (n=2,318) replicated associations at 12q24 within MSRB3/WIF1 (discovery + replication, rs17178006; p=5.3×10-11) and at 12q14 near HRK/FBXW8 (rs7294919; p=2.9×10-11). Remaining associations included one 2q24 SNP within DPP4 (rs6741949; p=2.9×10-7) and nine 9p33 SNPs within ASTN2 (rs7852872; p=1.0×10-7) that were also associated with HV (p<0.05) in a third younger, more heterogeneous sample (n=7,794). The ASTN2 SNP was also associated 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), enzymes targeted by new diabetes medications (DPP4), and neuronal migration (ASTN2), indicating novel genetic influences that influence hippocampal size and possibly the risk of cognitive decline and dementia.
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    Intermediate Phenotypes Identify Divergent Pathways to Alzheimer's Disease
    (Public Library of Science, 2010) Shulman, Joshua M.; Chibnik, Lori; Aubin, Cristin; Schneider, Julie A.; Bennett, David A.; De Jager, Philip
    Background: Recent genetic studies have identified a growing number of loci with suggestive evidence of association with susceptibility to Alzheimer's disease (AD). However, little is known of the role of these candidate genes in influencing intermediate phenotypes associated with a diagnosis of AD, including cognitive decline or AD neuropathologic burden. Methods/Principal Findings: Thirty-two single nucleotide polymorphisms (SNPs) previously implicated in AD susceptibility were genotyped in 414 subjects with both annual clinical evaluation and completed brain autopsies from the Religious Orders Study and the Rush Memory and Aging Project. Regression analyses evaluated the relation of SNP genotypes to continuous measures of AD neuropathology and cognitive function proximate to death. A SNP in the zinc finger protein 224 gene (ZNF224, rs3746319) was associated with both global AD neuropathology (p = 0.009) and global cognition (p = 0.002); whereas, a SNP at the phosphoenolpyruvate carboxykinase locus (PCK1, rs8192708) was selectively associated with global cognition (p = 3.57×10−4). The association of ZNF224 with cognitive impairment was mediated by neurofibrillary tangles, whereas PCK1 largely influenced cognition independent of AD pathology, as well as Lewy bodies and infarcts. Conclusions/Significance: The findings support the association of several loci with AD, and suggest how intermediate phenotypes can enhance analysis of susceptibility loci in this complex genetic disorder.