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1.  Genome-Wide Association Meta-analysis of Neuropathologic Features of Alzheimer's Disease and Related Dementias 
PLoS Genetics  2014;10(9):e1004606.
Alzheimer's disease (AD) and related dementias are a major public health challenge and present a therapeutic imperative for which we need additional insight into molecular pathogenesis. We performed a genome-wide association study and analysis of known genetic risk loci for AD dementia using neuropathologic data from 4,914 brain autopsies. Neuropathologic data were used to define clinico-pathologic AD dementia or controls, assess core neuropathologic features of AD (neuritic plaques, NPs; neurofibrillary tangles, NFTs), and evaluate commonly co-morbid neuropathologic changes: cerebral amyloid angiopathy (CAA), Lewy body disease (LBD), hippocampal sclerosis of the elderly (HS), and vascular brain injury (VBI). Genome-wide significance was observed for clinico-pathologic AD dementia, NPs, NFTs, CAA, and LBD with a number of variants in and around the apolipoprotein E gene (APOE). GalNAc transferase 7 (GALNT7), ATP-Binding Cassette, Sub-Family G (WHITE), Member 1 (ABCG1), and an intergenic region on chromosome 9 were associated with NP score; and Potassium Large Conductance Calcium-Activated Channel, Subfamily M, Beta Member 2 (KCNMB2) was strongly associated with HS. Twelve of the 21 non-APOE genetic risk loci for clinically-defined AD dementia were confirmed in our clinico-pathologic sample: CR1, BIN1, CLU, MS4A6A, PICALM, ABCA7, CD33, PTK2B, SORL1, MEF2C, ZCWPW1, and CASS4 with 9 of these 12 loci showing larger odds ratio in the clinico-pathologic sample. Correlation of effect sizes for risk of AD dementia with effect size for NFTs or NPs showed positive correlation, while those for risk of VBI showed a moderate negative correlation. The other co-morbid neuropathologic features showed only nominal association with the known AD loci. Our results discovered new genetic associations with specific neuropathologic features and aligned known genetic risk for AD dementia with specific neuropathologic changes in the largest brain autopsy study of AD and related dementias.
Author Summary
Alzheimer's disease (AD) and related dementias are a major public health challenge and present a therapeutic imperative for which we need additional insight into molecular pathogenesis. We performed a genome-wide association study (GWAS), as well as an analysis of known genetic risk loci for AD dementia, using data from 4,914 brain autopsies. Genome-wide significance was observed for 7 genes and pathologic features of AD and related diseases. Twelve of the 22 genetic risk loci for clinically-defined AD dementia were confirmed in our pathologic sample. Correlation of effect sizes for risk of AD dementia with effect size for hallmark pathologic features of AD were strongly positive and linear. Our study discovered new genetic associations with specific pathologic features and aligned known genetic risk for AD dementia with specific pathologic changes in a large brain autopsy study of AD and related dementias.
doi:10.1371/journal.pgen.1004606
PMCID: PMC4154667  PMID: 25188341
2.  Intronic Polymorphisms Affecting Alternative Splicing of Human Dopamine D2 Receptor Are Associated with Cocaine Abuse 
Neuropsychopharmacology  2010;36(4):753-762.
The dopamine receptor D2 (encoded by DRD2) is implicated in susceptibility to mental disorders and cocaine abuse, but mechanisms responsible for this relationship remain uncertain. DRD2 mRNA exists in two main splice isoforms with distinct functions: D2 long (D2L) and D2 short (D2S, lacking exon 6), expressed mainly postsynaptically and presynaptically, respectively. Two intronic single-nucleotide polymorphisms (SNPs rs2283265 (intron 5) and rs1076560 (intron 6)) in high linkage disequilibrium (LD) with each other have been reported to alter D2S/D2L splicing and several behavioral traits in human subjects, such as memory processing. To assess the role of DRD2 variants in cocaine abuse, we measured levels of D2S and D2L mRNA in human brain autopsy tissues (prefrontal cortex and putamen) obtained from cocaine abusers and controls, and genotyped a panel of DRD2 SNPs (119 abusers and 95 controls). Robust effects of rs2283265 and rs1076560 on reducing formation of D2S relative to D2L were confirmed. The minor alleles of rs2283265/rs1076560 were considerably more frequent in Caucasians (18%) compared with African Americans (7%). Also, in Caucasians, rs2283265/rs1076560 minor alleles were significantly overrepresented in cocaine abusers compared with controls (rs2283265: 25 to 9%, respectively; p=0.001; OR=3.4 (1.7–7.1)). Several SNPs previously implicated in diverse clinical association studies are in high LD with rs2283265/rs1076560 and could have served as surrogate markers. Our results confirm the role of rs2283265/rs1076560 in D2 alternative splicing and support a strong role in susceptibility to cocaine abuse.
doi:10.1038/npp.2010.208
PMCID: PMC3055737  PMID: 21150907
alternative splicing; cocaine; dopamine; DRD2; D2S; human; addiction and substance abuse; dopamine; neurogenetics; psychostimulants; drd2; d2s; human; alternative splicing; cocaine
3.  Alpha Synuclein Protein Levels are Increased in Serum from Recently Abstinent Cocaine Abusers 
Drug and alcohol dependence  2007;94(1-3):246-250.
Alpha synuclein is increased in dopamine neurons of cocaine abusers and in rats whose alcohol preference is inbred. Recent studies have shown increased alpha-synuclein protein expression in serum of alcoholic patients that is linked with severity of alcohol craving. The aim of this study was to analyze the serum levels of alpha synuclein in healthy subjects and in recently abstinent cocaine abusers. Alpha synuclein protein expression was measured by enzyme-linked immunosorbent assay in serum specimens obtained from 38 recently abstinent cocaine dependent patients and 14 control subjects. The presence of cocaine dependence disorder was based on the Structured Clinical Interview (DSM-IV). Drug severity was assessed by the Addiction Severity Index ratings and composite measures. Scores of the intensity and frequency of cocaine craving episodes were obtained from the Minnesota Cocaine Craving Questionnaire. The serum concentrations of alpha synuclein in cocaine dependent patients were significantly higher as compared with age-matched drug-free controls (p < 0.001). Alpha synuclein levels in blood were significantly correlated with the intensity (r = 0.60, p < 0.001) and frequency (r = 0.64. p < 0.001) of cocaine craving and with thirty days of cocaine use in the prior month before entry to treatment (r = 0.56, p < 0.005). However, there was no correlation between the serum protein levels of alpha synuclein and age in either group. This report is the first demonstration of altered alpha synuclein levels in peripheral blood from cocaine abusers. These data agree with previous reports in postmortem brain of cocaine abusers and provide support for an association between alpha synuclein and cocaine dependence.
doi:10.1016/j.drugalcdep.2007.09.020
PMCID: PMC2366137  PMID: 18055133
Cocaine; serum; dopamine; craving; synuclein

Results 1-3 (3)