Larry D. Adams

Rare complement factor H variant associated with age-related macular degeneration in the Amish

PURPOSE Age-related macular degeneration is the leading cause of blindness among the adult population in the developed world. To further the understanding of this disease, we have studied the genetically isolated Amish population of Ohio and Indiana. METHODS Cumulative genetic risk scores were calculated using the 19 known allelic associations. Exome sequencing was performed in three members of a small Amish family with AMD who lacked the common risk alleles in complement factor H (CFH) and ARMS2/HTRA1. Follow-up genotyping and association analysis was performed in a cohort of 973 Amish individuals, including 95 with self-reported AMD. RESULTS The cumulative genetic risk score analysis generated a mean genetic risk score of 1.12 (95% confidence interval [CI]: 1.10, 1.13) in the Amish controls and 1.18 (95% CI: 1.13, 1.22) in the Amish cases. This mean difference in genetic risk scores is statistically significant (P = 0.0042). Exome sequencing identified a rare variant (P503A) in CFH. Association analysis in the remainder of the Amish sample revealed that the P503A variant is significantly associated with AMD (P = 9.27 × 10(-13)). Variant P503A was absent when evaluated in a cohort of 791 elderly non-Amish controls, and 1456 non-Amish cases. CONCLUSIONS Data from the cumulative genetic risk score analysis suggests that the variants reported by the AMDGene consortium account for a smaller genetic burden of disease in the Amish compared with the non-Amish Caucasian population. Using exome sequencing data, we identified a novel missense mutation that is shared among a densely affected nuclear Amish family and located in a gene that has been previously implicated in AMD risk.

Progression Rate From Intermediate to Advanced Age-Related Macular Degeneration Is Correlated With the Number of Risk Alleles at the CFH Locus.

Purpose Progression rate of age-related macular degeneration (AMD) varies substantially, yet its association with genetic variation has not been widely examined. Methods We tested whether progression rate from intermediate AMD to geographic atrophy (GA) or choroidal neovascularization (CNV) was correlated with genotype at seven single nucleotide polymorphisms (SNPs) in the four genes most strongly associated with risk of advanced AMD. Cox proportional hazards survival models examined the association between progression time and SNP genotype while adjusting for age and sex and accounting for variable follow-up time, right censored data, and repeated measures (left and right eyes). Results Progression rate varied with the number of risk alleles at the CFH:rs10737680 but not the CFH:rs1061170 (Y402H) SNP; individuals with two risk alleles progressed faster than those with one allele (hazard ratio [HR] = 1.61, 95% confidence interval [CI] = 1.08–2.40, P < 0.02, n = 547 eyes), although this was not significant after Bonferroni correction. This signal was likely driven by an association at the correlated protective variant, CFH:rs6677604, which tags the CFHR1-3 deletion; individuals with at least one protective allele progressed more slowly. Considering GA and CNV separately showed that the effect of CFH:rs10737680 was stronger for progression to CNV. Conclusions Results support previous findings that AMD progression rate is influenced by CFH, and suggest that variants within CFH may have different effects on risk versus progression. However, since CFH:rs10737680 was not significant after Bonferroni correction and explained only a relatively small portion of variation in progression rate beyond that explained by age, we suggest that additional factors contribute to progression.

IDENTIFYING A PROTECTIVE VARIANT THAT LOWERS THE RISK FOR DEVELOPING AD IN APOE-E4 CARRIERS

ory were conducted in the group of self-identified ‘non-Hispanic White’. Results:The group with African ancestry showed a continuous distribution between 10% and 94% (Figure 1b). Linear mixed models revealed a significant three-way interaction between time, percent African ancestry, and APOE4 status (p1⁄40.003), such that the impact of APOE4 on memory decline was most pronounced at lower percentages of African ancestry. Post-hoc analyses dividing the sample based on a median split of African ancestry confirmed the direction of the interaction, showing a significant effect of APOE4 on memory decline only in the low African ancestry group (b1⁄4-0.18, p<0.001) but not for the high African ancestry group (b1⁄40.02, p1⁄40.6) (Figure 2). Conclusions:A greater percentage of African ancestry is associated with a reduced effect of APOE4 on memory decline. Thus, different genetic risk factors may be more relevant to the prediction of cognitive decline in individuals with high African ancestry compared to individuals with low African Ancestry and self-identified ‘non-Hispanic White’.

CONTINUOUS COMMUNITY ENGAGEMENT IMPROVES RECRUITMENT OF OLDER AFRICAN AMERICANS FOR GENETIC STUDIES IN ALZHEIMER’S DISEASE

baseline MMSE variability and the association of pre-intervention MMSE variability with ADAS-Cog change at 52 weeks in the entire trial cohort, collapsed across treatment assignment. Results:Change on the MMSE from screening to baseline was assessed in 373 participants. On average, participants were 71.9 (SD1⁄47.9) years old; had completed 15.1 (SD1⁄43.0) years of education; and scored 18.1 (SD1⁄43.0) on the MMSE at screening. Average change on the MMSE from screening to baseline was -0.21 (SD1⁄42.60) points. Change scores were normally distributed around the mean, as shown in Figure 1; however, there were outliers, with some participant’s scores changing as much as 10-12 points. To evaluate whether pre-randomization cognitive variability was associated with study outcome, participants were divided into quartiles based on their screening-to-baseline MMSE change score. Quartiles of pre-randomization variability did not differ in change on the ADAS-Cog at 52 weeks (Figure 2; F(3,338)1⁄41.49; p1⁄40.22). Conclusions:In this trial cohort of mildto-moderate AD participants, variability in MMSE score from screening to baseline was normally distributed around a small mean change of -0.21 points. Pre-randomization variability was not associated with ADAS-Cog change at 52 weeks. These results suggest that potential trial participants need not be excluded from participation based upon pre-randomization variability on mental-status screening.

GENOME-WIDE LINKAGE ANALYSES OF AFRICAN AMERICAN FAMILIES SUPPORTS EVIDENCE OF LINKAGE TO CHROMOSOME 12

SNP-based association result. Results: Targeted gene based association analysis for DAG-pathway related candidate genes identified PNPLA2 (p-value1⁄46.55E-05) as significantly associated with CSF t-tau and p-tau levels after adjusting for multiple testing using the Bonferroni correction. In addition, AKAP13 (p-value1⁄46.40E-04) and LIPF(p-value 1⁄45.50E-04) were marginally associated with CSF Ab and p-tau levels, respectively. Conclusions: A DAG pathway-related gene PNPLA2 was associated with CSF t-tau and p-tau levels. PNPLA2 (patatin-like phospholipase domain containing 2) functions in lipid metabolism and signaling with genetic roles in autism and physiological contributions to aging. AKAP13, which was marginally associated with Ab levels, is known to phosphorylate tau. Studies of DAG metabolite species are planned and replication of the genetic associations will be important.

TRANSCRIPTOMIC ANALYSIS OF WHOLE BLOOD IN AFRICAN AMERICAN AND NON-HISPANIC WHITE ALZHEIMER DISEASE CASES AND CONTROLS

P1-144 TRANSCRIPTOMIC ANALYSIS OF WHOLE BLOOD IN AFRICAN AMERICAN AND NON-HISPANIC WHITE ALZHEIMER DISEASE CASES AND CONTROLS Anthony J. Griswold, Sathesh K. Sivasankaran, Olivia K. Gardner, Farid Rajabli, Kara L. Hamilton-Nelson, Sophie Rolati, Natalia K. Hofmann, Patrice L. Whitehead, Larry D. Adams, Goldie S. Byrd, Eden R. Martin, Michael L. Cuccaro, William S. Bush, Jonathan L. Haines, Jeffery M. Vance, Gary W. Beecham, Margaret A. Pericak-Vance, University of Miami, Miami, FL, USA; John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA; North Carolina A&T State University, Greensboro, NC, USA; Case Western Reserve University, Cleveland, OH, USA. Contact e-mail: agriswold@med.miami.edu

THE PUERTO RICAN ALZHEIMER DISEASE INITIATIVE (PRADI): INITIAL CLINICAL FINDINGS

that results in increased amyloid beta levels. Results:We will report our results and discuss how they relate to the relationship between these mutations and both chemokine and amyloid beta levels in mammalian cell lines. Conclusions: This work will allow us to examine the role that amyloid beta plays in the activation of pro-inflammatory responses by the chemokine receptors CCBP2 and CCLR2 and their respective mutants. This work could lead to a means of regulating amyloid beta production and expression which could lead to novel therapeutic solutions.

RESOURCE OF MULTIPLEX AFRICAN AMERICAN FAMILIES FOR WHOLE-GENOME SEQUENCING

identified X11L as an APP interacting protein (2). We have reported that X11L is expressed specifically in neurons (3), it regulates intracellular transport and metabolism of APP in vivo (4, 5), and the production and deposition of brain Ab in human type APP-Tg was enhanced in X11L-KO mouse (6). Taken together, X11L is involved in the cause of AD. Methods: To demonstrate whether X11L involves in the gene expressions related to AD onset, we tried to identify the ApoE4-X11L regulated genes. To identify them, comprehensive gene expression analyses by RNA-seq were performed using brains of WT, X11L-KO, human ApoE4 (hApoE4)KI, hApoE4-KI/X11L-KOmice. Results:We identified a group of genes whose expressions were regulated by ApoE4 and X11L. GO analysis revealed that these genes are involved in intracellular protein transport. We also analyzed the gene expressional differences between human subjects with ApoE3 and ApoE4 using publicly available data, and identified common genes observed in mouse brain analysis. Conclusions: These suggest that there is a set of genes regulated by ApoE4 and X11L, which are tightly correlated to the cause of AD.Wewill report further analyses of obtained data and will reveal how ApoE4 and X11L regulated genes are involved in the cause of AD. (1) Rhinn [2013] Nature 500, 4550); (2) Tomita [1999] J. Biol. Chem. 274, 2243-2254; (3)Motodate [2016] Brain Res. 1646, 227-234; (4) Sano [2006] J. Biol. Chem. 281, 37853-37860; (5) Saito [2008] J. Biol. Chem. 283, 3576335771; (6) Kondo [2010] Mol. Neurodegener. 5, 35

THE PUERTO RICO ALZHEIMER DISEASE INITIATIVE (PRADI): A MULTISOURCE ASCERTAINMENT APPROACH

Citation: Feliciano-Astacio BE, Celis K, Ramos J, Rajabli F, Adams LD, Rodriguez A, Rodriguez V, Bussies PL, Sierra C, Manrique P, Mena PR, Grana A, Prough M, Hamilton-Nelson KL, Feliciano N, Chinea A, Acosta H, McCauley JL, Vance JM, Beecham GW, Pericak-Vance MA and Cuccaro ML (2019) The Puerto Rico Alzheimer Disease Initiative (PRADI): A Multisource Ascertainment Approach. Front. Genet. 10:538. doi: 10.3389/fgene.2019.00538 The Puerto Rico Alzheimer Disease Initiative (PRADI): A Multisource Ascertainment Approach

PATIENT-DERIVED IPSC MODEL OF AN ABCA7 FRAMESHIFT DELETION ASSOCIATED WITH ALZHEIMER’S DISEASE IN AFRICAN AMERICANS

Background:Patients with early-onset Alzheimer’s disease (EOAD) are relatively rare. APP, PSEN1 and PSEN2, are major causative factors for the disease progression. Patient was a 37 years old male, who was diagnosed with AD with Parkinsonism. Methods: Due to the pathological overlap of between different neurodegenerative diseases, we performed a complex genetic profiling analysis by next generation sequencing (NGS) for 50 causative or risk factor genes. In silico studies and 3D modeling were also performed for the mutations. Results: We discovered a novel PSEN1 variant, G417A, located in the exon 12 in the 8 transmembrane region. This mutation may impair the splicing of PSEN1 transcriptome, since it is located adjacent to the splice site. Conclusions:PolyPhen and SIFT revealed PSEN1 G417A mutation as probably damaging, and 3D protein structure prediction revealed that it may result extra stress inside the TM region due to the higher hydrophobicity of alanine. Cell studies are currently ongoing to verify the role of mutation in AD progression.