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Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in non-European ancestry groups in genome-wide association studies (GWAS). We constructed and analyzed a multi-ancestry GWAS dataset in the Alzheimer Disease (AD) Genetics Consortium (ADGC) to test for novel shared and ancestry-specific AD susceptibility loci and evaluate underlying genetic architecture in 37,382 non-Hispanic White (NHW), 6,728 African American, 8,899 Hispanic (HIS), and 3,232 East Asian individuals, performing within-ancestry fixed-effects meta-analysis followed by a cross-ancestry random-effects meta-analysis. We identified 13 loci with cross-ancestry associations including known loci at/near CR1, BIN1, TREM2, CD2AP, PTK2B, CLU, SHARPIN, MS4A6A, PICALM, ABCA7, APOE and two novel loci not previously reported at 11p12 (LRRC4C) and 12q24.13 (LHX5-AS1). Reflecting the power of diverse ancestry in GWAS, we observed the SHARPIN locus using 7.1% the sample size of the original discovering single-ancestry GWAS (n=788,989). We additionally identified three GWS ancestry-specific loci at/near (PTPRK (P=2.4E10-8) and GRB14 (P=1.7E10-8) in HIS), and KIAA0825 (P=2.9E10-8 in NHW). Pathway analysis implicated multiple amyloid regulation pathways (strongest with Padjusted=1.6E10-4) and the classical complement pathway (Padjusted=1.3E10-3). Genes at/near our novel loci have known roles in neuronal development (LRRC4C, LHX5-AS1, and PTPRK) and insulin receptor activity regulation (GRB14). These findings provide compelling support for using traditionally-underrepresented populations for gene discovery, even with smaller sample sizes.

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Purpose: To synthesize anticonvulsant drug derivatives that target protease-activated receptor generated epileptic seizures.Method: Varieties of carbamazepine-based Schiff bases were designed with different aldehydes and ketones, and evaluated for in silico computer-aided drug design prediction of absorption, distribution, metabolism and excretion (ADME), and potential drug targets. The resultant compounds were synthesized and characterized by various spectroscopic techniques, including FTIR, 1H-NMR and 13CNMR, analysis. Thereafter, they were screened for antimicrobial, antioxidant and anticonvulsant potential.Results: Prominent anti-protease potential was shown by C7 and C3 compounds and the order of activity was C7 > C3 > C5 > C2 > C6 > C4 > C2 > C1 (p < 0.05). The anticonvulsant activity of C7 and C5 was comparable with the standard drug; C3, C4, C6 and C8 had mild activity while C1 and C4 showed the least activity. The synthesized compounds exhibited significant (p < 0.05) antioxidant potential (rank order: C3 > C4 > C5 > C7 > C8 > C6 > C1 > C2) and antimicrobial activity against S.aureus and B. bronchiseptica (rank order: C5 > C2 > C8 > C1 > C4 > C3 > C7).Conclusion: Synthesized derivatives retained their potential for anticonvulsant and antitrypsin activity, unlike their mother moiety, i.e., carbamazepine. The additional antibacterial activity effectively treats neurological disorders associated with bacterial infections.