Publications by authors named "Gary W Beecham"

75 Publications

Genome-Wide Linkage and Association Study of Childhood Gender Nonconformity in Males.

Arch Sex Behav 2021 Sep 13. Epub 2021 Sep 13.

John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.

Male sexual orientation is influenced by environmental and complex genetic factors. Childhood gender nonconformity (CGN) is one of the strongest correlates of homosexuality with substantial familiality. We studied brothers in families with two or more homosexual brothers (409 concordant sibling pairs in 384 families, as well as their heterosexual brothers), who self-recalled their CGN. To map loci for CGN, we conducted a genome-wide linkage scan (GWLS) using SNP genotypes. The strongest linkage peaks, each with significant or suggestive two-point LOD scores and multipoint LOD score support, were on chromosomes 5q31 (maximum two-point LOD = 4.45), 6q12 (maximum two-point LOD = 3.64), 7q33 (maximum two-point LOD = 3.09), and 8q24 (maximum two-point LOD = 3.67), with the latter not overlapping with previously reported strongest linkage region for male sexual orientation on pericentromeric chromosome 8. Family-based association analyses were used to identify associated variants in the linkage regions, with a cluster of SNPs (minimum association p = 1.3 × 10) found at the 5q31 linkage peak. Genome-wide, clusters of multiple SNPs in the 10 to 10 p-value range were found at chromosomes 5p13, 5q31, 7q32, 8p22, and 10q23, highlighting glutamate-related genes. This is the first reported GWLS and genome-wide association study on CGN. Further increasing genetic knowledge about CGN and its relationships to male sexual orientation should help advance our understanding of the biology of these associated traits.
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http://dx.doi.org/10.1007/s10508-021-02146-xDOI Listing
September 2021

Genomic evidence consistent with antagonistic pleiotropy may help explain the evolutionary maintenance of same-sex sexual behaviour in humans.

Nat Hum Behav 2021 09 23;5(9):1251-1258. Epub 2021 Aug 23.

Department of Psychiatry, Amsterdam UMC location AMC, University of Amsterdam, Amsterdam, the Netherlands.

Human same-sex sexual behaviour (SSB) is heritable, confers no immediately obvious direct reproductive or survival benefit and can divert mating effort from reproductive opportunities. This presents a Darwinian paradox: why has SSB been maintained despite apparent selection against it? We show that genetic effects associated with SSB may, in individuals who only engage in opposite-sex sexual behaviour (OSB individuals), confer a mating advantage. Using results from a recent genome-wide association study of SSB and a new genome-wide association study on number of opposite-sex sexual partners in 358,426 individuals, we show that, among OSB individuals, genetic effects associated with SSB are associated with having more opposite-sex sexual partners. Computer simulations suggest that such a mating advantage for alleles associated with SSB could help explain how it has been evolutionarily maintained. Caveats include the cultural specificity of our UK and US samples, the societal regulation of sexual behaviour in these populations, the difficulty of measuring mating success and the fact that measured variants capture a minority of the total genetic variation in the traits.
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http://dx.doi.org/10.1038/s41562-021-01168-8DOI Listing
September 2021

Genome-Wide Linkage Study Meta-Analysis of Male Sexual Orientation.

Arch Sex Behav 2021 Jun 2. Epub 2021 Jun 2.

John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.

Male sexual orientation is a scientifically and socially important trait shown by family and twin studies to be influenced by environmental and complex genetic factors. Individual genome-wide linkage studies (GWLS) have been conducted, but not jointly analyzed. Two main datasets account for > 90% of the published GWLS concordant sibling pairs on the trait and are jointly analyzed here: MGSOSO (Molecular Genetic Study of Sexual Orientation; 409 concordant sibling pairs in 384 families, Sanders et al. (2015)) and Hamer (155 concordant sibling pairs in 145 families, Mustanski et al. (2005)). We conducted multipoint linkage analyses with Merlin on the datasets separately since they were genotyped differently, integrated genetic marker positions, and combined the resultant LOD (logarithm of the odds) scores at each 1 cM grid position. We continue to find the strongest linkage support at pericentromeric chromosome 8 and chromosome Xq28. We also incorporated the remaining published GWLS dataset (on 55 families) by using meta-analytic approaches on published summary statistics. The meta-analysis has maximized the positional information from GWLS of currently available family resources and can help prioritize findings from genome-wide association studies (GWAS) and other approaches. Although increasing evidence highlights genetic contributions to male sexual orientation, our current understanding of contributory loci is still limited, consistent with the complexity of the trait. Further increasing genetic knowledge about male sexual orientation, especially via large GWAS, should help advance our understanding of the biology of this important trait.
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http://dx.doi.org/10.1007/s10508-021-02035-3DOI Listing
June 2021

Genomewide Association Studies of LRRK2 Modifiers of Parkinson's Disease.

Ann Neurol 2021 07 17;90(1):76-88. Epub 2021 May 17.

23andMe, Inc., Sunnyvale, CA.

Objective: The aim of this study was to search for genes/variants that modify the effect of LRRK2 mutations in terms of penetrance and age-at-onset of Parkinson's disease.

Methods: We performed the first genomewide association study of penetrance and age-at-onset of Parkinson's disease in LRRK2 mutation carriers (776 cases and 1,103 non-cases at their last evaluation). Cox proportional hazard models and linear mixed models were used to identify modifiers of penetrance and age-at-onset of LRRK2 mutations, respectively. We also investigated whether a polygenic risk score derived from a published genomewide association study of Parkinson's disease was able to explain variability in penetrance and age-at-onset in LRRK2 mutation carriers.

Results: A variant located in the intronic region of CORO1C on chromosome 12 (rs77395454; p value = 2.5E-08, beta = 1.27, SE = 0.23, risk allele: C) met genomewide significance for the penetrance model. Co-immunoprecipitation analyses of LRRK2 and CORO1C supported an interaction between these 2 proteins. A region on chromosome 3, within a previously reported linkage peak for Parkinson's disease susceptibility, showed suggestive associations in both models (penetrance top variant: p value = 1.1E-07; age-at-onset top variant: p value = 9.3E-07). A polygenic risk score derived from publicly available Parkinson's disease summary statistics was a significant predictor of penetrance, but not of age-at-onset.

Interpretation: This study suggests that variants within or near CORO1C may modify the penetrance of LRRK2 mutations. In addition, common Parkinson's disease associated variants collectively increase the penetrance of LRRK2 mutations. ANN NEUROL 2021;90:82-94.
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http://dx.doi.org/10.1002/ana.26094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252519PMC
July 2021

Linkage of Alzheimer disease families with Puerto Rican ancestry identifies a chromosome 9 locus.

Neurobiol Aging 2021 08 28;104:115.e1-115.e7. Epub 2021 Feb 28.

John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA; Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA.

The genetic admixture of Caribbean Hispanics provides an opportunity to discover novel genetic factors in Alzheimer disease (AD). We sought to identify genetic variants for AD through a family-based design using the Puerto Rican (PR) Alzheimer Disease Initiative (PRADI). Whole-genome sequencing (WGS) and parametric linkage analysis were performed for 100 individuals from 23 multiplex PRADI families. Variants were prioritized by minor allele frequency (<0.01), functional potential [combined annotation dependent depletion score (CADD) >10], and co-segregation with AD. Variants were further ranked using an independent PR case-control WGS dataset (PR10/66). A genome-wide significant linkage peak was found in 9p21 with a heterogeneity logarithm of the odds score (HLOD) >5.1, which overlaps with an AD linkage region from two published independent studies. The region harbors C9orf72, but no expanded repeats were observed in the families. Seven variants prioritized by the PRADI families also displayed evidence for association in the PR10/66 (p < 0.05), including a missense variant in UNC13B. Our study demonstrated the importance of family-based design and WGS in genetic study of AD.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.02.019DOI Listing
August 2021

Response to Comment on "Large-scale GWAS reveals insights into the genetic architecture of same-sex sexual behavior".

Science 2021 03;371(6536)

Centre for Psychology and Evolution, School of Psychology, University of Queensland, St. Lucia, Brisbane, QLD 4072, Australia.

Hamer argue that the variable "ever versus never had a same-sex partner" does not capture the complexity of human sexuality. We agree and said so in our paper. But Hamer neglect to mention that we also reported follow-up analyses showing substantial overlap of the genetic influences on our main variable and on more nuanced measures of sexual behavior, attraction, and identity.
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http://dx.doi.org/10.1126/science.aba5693DOI Listing
March 2021

Dissecting the role of Amerindian genetic ancestry and the ApoE ε4 allele on Alzheimer disease in an admixed Peruvian population.

Neurobiol Aging 2021 05 10;101:298.e11-298.e15. Epub 2020 Dec 10.

John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA; Dr. John Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA. Electronic address:

Alzheimer disease (AD) is the leading cause of dementia in the elderly and occurs in all ethnic and racial groups. The apolipoprotein E (ApoE) ε4 is the most significant genetic risk factor for late-onset AD and shows the strongest effect among East Asian populations followed by non-Hispanic white populations and has a relatively lower effect in African descent populations. Admixture analysis in the African American and Puerto Rican populations showed that the variation in ε4 risk is correlated with the genetic ancestral background local to the ApoE gene. Native American populations are substantially underrepresented in AD genetic studies. The Peruvian population with up to ~80 of Amerindian (AI) ancestry provides a unique opportunity to assess the role of AI ancestry in AD. In this study, we assess the effect of the ApoE ε4 allele on AD in the Peruvian population. A total of 79 AD cases and 128 unrelated cognitive healthy controls from Peruvian population were included in the study. Genome-wide genotyping was performed using the Illumina Global screening array v2.0. Global ancestry and local ancestry analyses were assessed. The effect of the ApoE ε4 allele on AD was tested using a logistic regression model by adjusting for age, gender, and population substructure (first 3 principal components). Results showed that the genetic ancestry surrounding the ApoE gene is predominantly AI (60.6%) and the ε4 allele is significantly associated with increased risk of AD in the Peruvian population (odds ratio = 5.02, confidence interval: 2.3-12.5, p-value = 2e-4). Our results showed that the risk for AD from ApoE ε4 in Peruvians is higher than we have observed in non-Hispanic white populations. Given the high admixture of AI ancestry in the Peruvian population, it suggests that the AI genetic ancestry local to the ApoE gene is contributing to a strong risk for AD in ε4 carriers. Our data also support the findings of an interaction between the genetic risk allele ApoE ε4 and the ancestral backgrounds located around the genomic region of ApoE gene.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8122013PMC
May 2021

Increased APOE ε4 expression is associated with the difference in Alzheimer's disease risk from diverse ancestral backgrounds.

Alzheimers Dement 2021 07 1;17(7):1179-1188. Epub 2021 Feb 1.

John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, Florida, USA.

Introduction: Apolipoprotein E (APOE) ε4 confers less risk for Alzheimer's disease (AD) in carriers with African local genomic ancestry (ALA) than APOE ε4 carriers with European local ancestry (ELA). Cell type specific transcriptional variation between the two local ancestries (LAs) could contribute to this disease risk differences.

Methods: Single-nucleus RNA sequencing was performed on frozen frontal cortex of homozygous APOE ε4/ε4 AD patients: seven with ELA, four with ALA.

Results: A total of 60,908 nuclei were sequenced. Within the LA region (chr19:44-46Mb), APOE was the gene most differentially expressed, with ELA carriers having significantly more expression (overall P < 1.8E ) in 24 of 32 cell clusters. The transcriptome of one astrocyte cluster, with high APOE ε4 expression and specific to ELA, is suggestive of A1 reactive astrocytes.

Discussion: AD patients with ELA expressed significantly greater levels of APOE than ALA APOE ε4 carriers. These differences in APOE expression could contribute to the reduced risk for AD seen in African APOE ε4 carriers.
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http://dx.doi.org/10.1002/alz.12287DOI Listing
July 2021

Late-onset vs nonmendelian early-onset Alzheimer disease: A distinction without a difference?

Neurol Genet 2020 Oct 6;6(5):e512. Epub 2020 Oct 6.

Taub Institute for Research on Alzheimer's Disease and the Aging Brain (C.R.), Gertrude H. Sergievsky Center (C.R.), Department of Neurology (C.R.), and Department of Epidemiology (C.R.), College of Physicians and Surgeons, Columbia University, New York, NY; Tanz Centre for Research in Neurodegenerative Disease (E.R.), University of Toronto, ON, Canada; and The John P. Hussman Institute for Human Genomics (G.W.B.), University of Miami, FL.

There is mounting evidence that only a small fraction of early-onset Alzheimer disease cases (onset <65 years) are explained by known mutations. Even multiplex families with early onset often also have late-onset cases, suggesting that the commonly applied categorization of Alzheimer disease into early- and late-onset forms may not reflect distinct underlying etiology. Nevertheless, this categorization continues to govern today's research and the design of clinical trials. The aim of this review is to evaluate this categorization by providing a comprehensive, critical review of reported clinical, neuropathologic, and genomic characteristics of both onset-based subtypes and explore potential overlap between both categories. The article will lay out the need to comprehensively assess the phenotypic, neuropathologic, and molecular variability in Alzheimer disease and identify factors explaining the observed significant variation in onset age in persons with and without known mutations. The article will critically review ongoing large-scale genomic efforts in Alzheimer disease research (e.g., Alzheimer Disease Sequencing Project, Dominantly Inherited Alzheimer Network, Alzheimer Disease Neuroimaging Initiative) and their shortcomings to disentangle the delineation of unexplained nonmendelian early-onset from late-onset and mendelian forms of Alzheimer disease. In addition, it will outline specific approaches including epigenetic research through which a comprehensive characterization of this delineation can be achieved.
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http://dx.doi.org/10.1212/NXG.0000000000000512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673282PMC
October 2020

Immune and Inflammatory Pathways Implicated by Whole Blood Transcriptomic Analysis in a Diverse Ancestry Alzheimer's Disease Cohort.

J Alzheimers Dis 2020 ;76(3):1047-1060

John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA.

Background: Significant work has identified genetic variants conferring risk and protection for Alzheimer's disease (AD), but functional effects of these variants is lacking, particularly in under-represented ancestral populations. Expression studies performed in easily accessible tissue, such as whole blood, can recapitulate some transcriptional changes occurring in brain and help to identify mechanisms underlying neurodegenerative processes.

Objective: We aimed to identify transcriptional differences between AD cases and controls in a cohort of diverse ancestry.

Methods: We analyzed the protein coding transcriptome using RNA sequencing from peripheral blood collected from 234 African American (AA) (115 AD, 119 controls) and 240 non-Hispanic Whites (NHW) (121 AD, 119 controls). To identify case-control differentially expressed genes and pathways, we performed stratified, joint, and interaction analyses using linear regression models within and across ancestral groups followed by pathway and gene set enrichment analyses.

Results: Overall, we identified 418 (291 upregulated, 127 downregulated) and 488 genes (352 upregulated, 136 downregulated) differentially expressed in the AA and NHW datasets, respectively, with only 16 genes commonly differentially expressed in both ancestral groups. Joint analyses provided greater power to detect case-control differences and identified 1,102 differentially expressed genes between cases and controls (812 upregulated, 290 downregulated). Interaction analysis identified only 27 genes with different effects in AA compared to NHW. Pathway and gene-set enrichment analyses revealed differences in immune response-related pathways that were enriched across the analyses despite different underlying gene sets.

Conclusion: These results support the hypothesis of converging underlying pathophysiological processes in AD across ancestral groups.
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http://dx.doi.org/10.3233/JAD-190855DOI Listing
June 2021

Use of local genetic ancestry to assess -523' and risk for Alzheimer disease.

Neurol Genet 2020 Apr 3;6(2):e404. Epub 2020 Mar 3.

John P. Hussman Institute for Human Genomics (P.L.B., F.R., A.G., D.A.D., P.W., L.D.A., P.R.M., M.C., G.W.B., M.A.P.-V., J.I.Y., J.M.V.), Miller School of Medicine, University of Miami; Dr. John T. MacDonald Foundation Department of Human Genetics (A.G., M.C., G.W.B., M.A.P.-V., J.I.Y., J.M.V.), Miller School of Medicine, University of Miami; Department of Population and Quantitative Health Sciences (J.L.H.), Institute for Computational Biology, Case Western Reserve University School of Medicine, Cleveland, OH; and Wake Forest School of Medicine (G.S.B.), Bowman Gray Center for Medical Education, Winston-Salem, NC.

Objective: Here, we re-examine -523' as a race/ethnicity-specific risk modifier for late-onset Alzheimer disease (LOAD) with adjustment for local genomic ancestry (LGA) in (4 haplotypes.

Methods: The -523' size was determined by fragment analysis and whole genome sequencing in homozygous 3 and 4 haplotypes of African (AF) or European (EUR) ancestry. The risk for LOAD was assessed within groups by allele size.

Results: The -523' length did not modify risk for LOAD in haplotypes with EUR or AF LGA. Increasing length of -523' was associated with a significantly reduced risk for LOAD in EUR ε3 haplotypes.

Conclusions: Adjustment for LGA confirms that -523' cannot explain the strong differential risk for LOAD between ε4 with EUR and AF LGA. Our study does confirm previous reports that increasing allele length of the repeat is associated with decreased risk for LOAD in carriers of homozygous ε3 alleles and demonstrates that this effect is occurring in those individuals with the EUR LGA ε3 allele haplotype.
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http://dx.doi.org/10.1212/NXG.0000000000000404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7164968PMC
April 2020

Exceptionally low likelihood of Alzheimer's dementia in APOE2 homozygotes from a 5,000-person neuropathological study.

Nat Commun 2020 02 3;11(1):667. Epub 2020 Feb 3.

Department of Epidemiology, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195, USA.

Each additional copy of the apolipoprotein E4 (APOE4) allele is associated with a higher risk of Alzheimer's dementia, while the APOE2 allele is associated with a lower risk of Alzheimer's dementia, it is not yet known whether APOE2 homozygotes have a particularly low risk. We generated Alzheimer's dementia odds ratios and other findings in more than 5,000 clinically characterized and neuropathologically characterized Alzheimer's dementia cases and controls. APOE2/2 was associated with a low Alzheimer's dementia odds ratios compared to APOE2/3 and 3/3, and an exceptionally low odds ratio compared to APOE4/4, and the impact of APOE2 and APOE4 gene dose was significantly greater in the neuropathologically confirmed group than in more than 24,000 neuropathologically unconfirmed cases and controls. Finding and targeting the factors by which APOE and its variants influence Alzheimer's disease could have a major impact on the understanding, treatment and prevention of the disease.
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http://dx.doi.org/10.1038/s41467-019-14279-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6997393PMC
February 2020

Large-scale GWAS reveals insights into the genetic architecture of same-sex sexual behavior.

Science 2019 08;365(6456)

Centre for Psychology and Evolution, School of Psychology, University of Queensland, St. Lucia, Brisbane QLD 4072, Australia.

Twin and family studies have shown that same-sex sexual behavior is partly genetically influenced, but previous searches for specific genes involved have been underpowered. We performed a genome-wide association study (GWAS) on 477,522 individuals, revealing five loci significantly associated with same-sex sexual behavior. In aggregate, all tested genetic variants accounted for 8 to 25% of variation in same-sex sexual behavior, only partially overlapped between males and females, and do not allow meaningful prediction of an individual's sexual behavior. Comparing these GWAS results with those for the proportion of same-sex to total number of sexual partners among nonheterosexuals suggests that there is no single continuum from opposite-sex to same-sex sexual behavior. Overall, our findings provide insights into the genetics underlying same-sex sexual behavior and underscore the complexity of sexuality.
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http://dx.doi.org/10.1126/science.aat7693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7082777PMC
August 2019

Genome-wide brain DNA methylation analysis suggests epigenetic reprogramming in Parkinson disease.

Neurol Genet 2019 Aug 24;5(4):e342. Epub 2019 Jun 24.

John P. Hussman Institute for Human Genomics (J.I.Y., S.K.S., A.A., A.M., D.M.D., G.W.B., E.R.M., M.P.-V., W.K.S., J.M.V.), Miller School of Medicine, University of Miami; Department of Public Health Sciences (L.W.), Division of Biostatistics, Miller School of Medicine, University of Miami; Department of Neurology (D.A.D., D.C.M.), Miller School of Medicine, University of Miami; Department of Pathology (C.K.P.), Miller School of Medicine, University of Miami, FL; and Department of Pathology (T.J.M.), Stanford University, CA.

Objective: Given the known strong relationship of DNA methylation with environmental exposure, we investigated whether brain regions affected in Parkinson disease (PD) were differentially methylated between PD cases and controls.

Methods: DNA chip arrays were used to perform a genome-wide screen of DNA methylation on the dorsal motor nucleus of the vagus (DMV), substantia nigra (SN), and cingulate gyrus (CG) of pathologically confirmed PD cases and controls selected using the criteria of Beecham et al. Analysis examined differentially methylated regions (DMRs) between cases and controls for each brain area. RNA sequencing and pathway analysis were also performed for each brain area.

Results: Thirty-eight PD cases and 41 controls were included in the analysis. Methylation studies revealed 234 significant DMR in the DMV, 44 in the SN, and 141 in the CG between cases and controls (Sidak < 0.05). Pathway analysis of these genes showed significant enrichment for the Wnt signaling pathway (FDR < 0.01).

Conclusions: Our data suggest that significant DNA methylation changes exist between cases and controls in PD, especially in the DMV, one of the areas affected earliest in PD. The etiology of these methylation changes is not yet known, but the predominance of methylation changes occurring in the DMV supports the hypothesis that vagus nerve function, perhaps involving the gastrointestinal system, is important in PD pathogenesis. These data also give independent support that genes involved in Wnt signaling are a likely factor in the neurodegenerative processes of PD.
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http://dx.doi.org/10.1212/NXG.0000000000000342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6659138PMC
August 2019

The Puerto Rico Alzheimer Disease Initiative (PRADI): A Multisource Ascertainment Approach.

Front Genet 2019 19;10:538. Epub 2019 Jun 19.

John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, United States.

Introduction: Puerto Ricans, the second largest Latino group in the continental US, are underrepresented in genomic studies of Alzheimer disease (AD). To increase representation of this group in genomic studies of AD, we developed a multisource ascertainment approach to enroll AD patients, and their family members living in Puerto Rico (PR) as part of the Alzheimer's Disease Sequencing Project (ADSP), an international effort to advance broader personalized/precision medicine initiatives for AD across all populations.

Methods: The Puerto Rico Alzheimer Disease Initiative (PRADI) multisource ascertainment approach was developed to recruit and enroll Puerto Rican adults aged 50 years and older for a genetic research study of AD, including individuals with cognitive decline (AD, mild cognitive impairment), their similarly, aged family members, and cognitively healthy unrelated individuals age 50 and up. Emphasizing identification and relationship building with key stakeholders, we conducted ascertainment across the island. In addition to reporting on PRADI ascertainment, we detail admixture analysis for our cohort by region, group differences in age of onset, cognitive level by region, and ascertainment source.

Results: We report on 674 individuals who met standard eligibility criteria [282 AD-affected participants (42% of the sample), 115 individuals with mild cognitive impairment (MCI) (17% of the sample), and 277 cognitively healthy individuals (41% of the sample)]. There are 43 possible multiplex families (10 families with 4 or more AD-affected members and 3 families with 3 AD-affected members). Most individuals in our cohort were ascertained from the Metro, Bayamón, and Caguas health regions. Across health regions, we found differences in ancestral backgrounds, and select clinical traits.

Discussion: The multisource ascertainment approach used in the PRADI study highlights the importance of enlisting a broad range of community resources and providers. Preliminary results provide important information about our cohort that will be useful as we move forward with ascertainment. We expect that results from the PRADI study will lead to a better understanding of genetic risk for AD among this population.
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http://dx.doi.org/10.3389/fgene.2019.00538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6593074PMC
June 2019

RNA editing alterations in a multi-ethnic Alzheimer disease cohort converge on immune and endocytic molecular pathways.

Hum Mol Genet 2019 09;28(18):3053-3061

John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.

Little is known about the post-transcriptional mechanisms that modulate the genetic effects in the molecular pathways underlying Alzheimer disease (AD), and even less is known about how these changes might differ across diverse populations. RNA editing, the process that alters individual bases of RNA, may contribute to AD pathogenesis due to its roles in neuronal development and immune regulation. Here, we pursued one of the first transcriptome-wide RNA editing studies in AD by examining RNA sequencing data from individuals of both African-American (AA) and non-Hispanic White (NHW) ethnicities. Whole transcriptome RNA sequencing and RNA editing analysis were performed on peripheral blood specimens from 216 AD cases (105 AA, 111 NHW) and 212 gender matched controls (105 AA, 107 NHW). 449 positions in 254 genes and 723 positions in 371 genes were differentially edited in AA and NHW, respectively. While most differentially edited sites localized to different genes in AA and NHW populations, these events converged on the same pathways across both ethnicities, especially endocytic and inflammatory response pathways. Furthermore, these differentially edited sites were preferentially predicted to disrupt miRNA binding and induce nonsynonymous coding changes in genes previously associated with AD in molecular studies, including PAFAH1B2 and HNRNPA1. These findings suggest RNA editing is an important post-transcriptional regulatory program in AD pathogenesis.
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http://dx.doi.org/10.1093/hmg/ddz110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6737295PMC
September 2019

Modifier Gene Candidates in Charcot-Marie-Tooth Disease Type 1A: A Case-Only Genome-Wide Association Study.

J Neuromuscul Dis 2019 ;6(2):201-211

Department for Human Genetics and Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA.

Background: Charcot-Marie-Tooth disease type 1A (CMT1A) is caused by a uniform 1.5-Mb duplication on chromosome 17p, which includes the PMP22 gene. Patients often present the classic neuropathy phenotype, but also with high clinical variability.

Objective: We aimed to identify genetic variants that are potentially associated with specific clinical outcomes in CMT1A.

Methods: We genotyped over 600,000 genomic markers using DNA samples from 971 CMT1A patients and performed a case-only genome-wide association study (GWAS) to identify potential genetic association in a subset of 644 individuals of European ancestry. A total of 14 clinical outcomes were analyzed in this study.

Results: The analyses yielded suggestive association signals in four clinical outcomes: difficulty with eating utensils (lead SNP rs4713376, chr6 : 30773314, P = 9.91×10-7, odds ratio = 3.288), hearing loss (lead SNP rs7720606, chr5 : 126551732, P = 2.08×10-7, odds ratio = 3.439), decreased ability to feel (lead SNP rs17629990, chr4 : 171224046, P = 1.63×10-7, odds ratio = 0.336), and CMT neuropathy score (lead SNP rs12137595, chr1 : 4094068, P = 1.14×10-7, beta = 3.014).

Conclusions: While the results require validation in future genetic and functional studies, the detected association signals may point to novel genetic modifiers in CMT1A.
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http://dx.doi.org/10.3233/JND-190377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6597974PMC
December 2019

Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing.

Nat Genet 2019 03 28;51(3):414-430. Epub 2019 Feb 28.

Research Center and Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades-Universitat Internacional de Catalunya, Barcelona, Spain.

Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.
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http://dx.doi.org/10.1038/s41588-019-0358-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463297PMC
March 2019

Variation in SIPA1L2 is correlated with phenotype modification in Charcot- Marie- Tooth disease type 1A.

Ann Neurol 2019 03;85(3):316-330

Department for Human Genetics and Hussman Institute for Human Genomics, University of Miami, Miami, FL.

Objective: Genetic modifiers in rare disease have long been suspected to contribute to the considerable variance in disease expression, including Charcot-Marie-Tooth disease type 1A (CMT1A). To address this question, the Inherited Neuropathy Consortium collected a large standardized sample of such rare CMT1A patients over a period of 8 years. CMT1A is caused in most patients by a uniformly sized 1.5 Mb duplication event involving the gene PMP22.

Methods: We genotyped DNA samples from 971 CMT1A patients on Illumina BeadChips. Genome-wide analysis was performed in a subset of 330 of these patients, who expressed the extremes of a hallmark symptom: mild and severe foot dorsiflexion strength impairment. SIPA1L2 (signal-induced proliferation-associated 1 like 2), the top identified candidate modifier gene, was expressed in the peripheral nerve, and our functional studies identified and confirmed interacting proteins using coimmunoprecipitation analysis, mass spectrometry, and immunocytochemistry. Chromatin immunoprecipitation and in vitro siRNA experiments were used to analyze gene regulation.

Results: We identified significant association of 4 single nucleotide polymorphisms (rs10910527, rs7536385, rs4649265, rs1547740) in SIPA1L2 with foot dorsiflexion strength (p < 1 × 10 ). Coimmunoprecipitation and mass spectroscopy studies identified β-actin and MYH9 as SIPA1L2 binding partners. Furthermore, we show that SIPA1L2 is part of a myelination-associated coexpressed network regulated by the master transcription factor SOX10. Importantly, in vitro knockdown of SIPA1L2 in Schwannoma cells led to a significant reduction of PMP22 expression, hinting at a potential strategy for drug development.

Interpretation: SIPA1L2 is a potential genetic modifier of CMT1A phenotypic expressions and offers a new pathway to therapeutic interventions. ANN NEUROL 2019;85:316-330.
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http://dx.doi.org/10.1002/ana.25426DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263419PMC
March 2019

Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting.

Neurology 2019 Jan 16. Epub 2019 Jan 16.

Objective: To explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts.

Methods: We performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n = 20,949) from 5 ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6,862; 1,483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI.

Results: The mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, = 1.77 × 10; and LINC00539/ZDHHC20, = 5.82 × 10. Both have been associated with blood pressure (BP)-related phenotypes, but did not replicate in the smaller follow-up sample or show associations with related phenotypes. Age- and sex-adjusted associations with BI and SSBI were observed for BP traits ( value for BI, = 9.38 × 10; = 5.23 × 10 for hypertension), smoking ( = 4.4 × 10; = 1.2 × 10), diabetes ( = 1.7 × 10; = 2.8 × 10), previous cardiovascular disease ( = 1.0 × 10; = 2.3 × 10), stroke ( = 3.9 × 10; = 3.2 × 10), and MRI-defined white matter hyperintensity burden ( = 1.43 × 10; = 3.16 × 10), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI ( ≤ 0.0022), without indication of directional pleiotropy.

Conclusion: In this multiethnic GWAS meta-analysis, including over 20,000 population-based participants, we identified genetic risk loci for BI requiring validation once additional large datasets become available. High BP, including genetically determined, was the most significant modifiable, causal risk factor for BI.
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http://dx.doi.org/10.1212/WNL.0000000000006851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369905PMC
January 2019

Rare genetic variation implicated in non-Hispanic white families with Alzheimer disease.

Neurol Genet 2018 Dec 21;4(6):e286. Epub 2018 Nov 21.

John P. Hussman Institute for Human Genomics (G.W.B., J.J., K.H.-N., B.K., E.R.M., F.R., M.A.P.-V.), University of Miami, Miller School of Medicine; Dr. John T. Macdonald Foundation Department of Human Genetics (G.W.B., E.R.M., M.A.P.-V.), University of Miami, Miller School of Medicine, FL; The Taub Institute for Research on Alzheimer's Disease and the Aging Brain (B.V., S.B., C.R., R.M.), Columbia University; The Gertrude H. Segievsky Center (B.V., S.B., C.R., R.M.), Columbia University, New York Presbyterian Hospital; Division of Medical Genetics (E. Blue, E.W.), Department of Medicine, University of Washington, Seattle; Institute for Computational Biology (W.B., J.L.H.), Case Western Reserve University, Cleveland, OH; Department of Neurology (A.D., S.S., L.A.F.), Boston University School of Medicine; Department of Biostatistics (A.D., S.S., L.A.F.), Boston University School of Medicine, MA; School of Medicine (A.N., G.S.), University of Pennsylvania, Philadelphia; Department of Biostatistics (T.T., E.W.), University of Washington, Seattle; Erasmus Medical University (C.D.), Rotterdam, The Netherlands; Icahn School of Medicine at Mount Sinai (A.G.), New York, NY; Department of Medicine (L.A.F.), Boston University School of Medicine, MA; and University of Texas (E. Boerwinkle), Houston.

Objective: To identify genetic variation influencing late-onset Alzheimer disease (LOAD), we used a large data set of non-Hispanic white (NHW) extended families multiply-affected by LOAD by performing whole genome sequencing (WGS).

Methods: As part of the Alzheimer Disease Sequencing Project, WGS data were generated for 197 NHW participants from 42 families (affected individuals and unaffected, elderly relatives). A two-pronged approach was taken. First, variants were prioritized using heterogeneity logarithm of the odds (HLOD) and family-specific LOD scores as well as annotations based on function, frequency, and segregation with disease. Second, known Alzheimer disease (AD) candidate genes were assessed for rare variation using a family-based association test.

Results: We identified 41 rare, predicted-damaging variants that segregated with disease in the families that contributed to the HLOD or family-specific LOD regions. These included a variant in nitric oxide synthase 1 adaptor protein that segregates with disease in a family with 7 individuals with AD, as well as variants in , and . Rare-variant association identified 2 LOAD candidate genes associated with disease in these families: (-values = 0.001) and (-value = 0.009). These genes still showed association while controlling for common index variants, indicating the rare-variant signal is distinct from common variation that initially identified the genes as candidates.

Conclusions: We identified multiple genes with putative damaging rare variants that segregate with disease in multiplex AD families and showed that rare variation may influence AD risk at AD candidate genes. These results identify novel AD candidate genes and show a role for rare variation in LOAD etiology, even at genes previously identified by common variation.
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http://dx.doi.org/10.1212/NXG.0000000000000286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278241PMC
December 2018

Ancestral origin of ApoE ε4 Alzheimer disease risk in Puerto Rican and African American populations.

PLoS Genet 2018 12 5;14(12):e1007791. Epub 2018 Dec 5.

John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, Florida, United States of America.

The ApoE ε4 allele is the most significant genetic risk factor for late-onset Alzheimer disease. The risk conferred by ε4, however, differs across populations, with populations of African ancestry showing lower ε4 risk compared to those of European or Asian ancestry. The cause of this heterogeneity in risk effect is currently unknown; it may be due to environmental or cultural factors correlated with ancestry, or it may be due to genetic variation local to the ApoE region that differs among populations. Exploring these hypotheses may lead to novel, population-specific therapeutics and risk predictions. To test these hypotheses, we analyzed ApoE genotypes and genome-wide array data in individuals from African American and Puerto Rican populations. A total of 1,766 African American and 220 Puerto Rican individuals with late-onset Alzheimer disease, and 3,730 African American and 169 Puerto Rican cognitively healthy individuals (> 65 years) participated in the study. We first assessed average ancestry across the genome ("global" ancestry) and then tested it for interaction with ApoE genotypes. Next, we assessed the ancestral background of ApoE alleles ("local" ancestry) and tested if ancestry local to ApoE influenced Alzheimer disease risk while controlling for global ancestry. Measures of global ancestry showed no interaction with ApoE risk (Puerto Rican: p-value = 0.49; African American: p-value = 0.65). Conversely, ancestry local to the ApoE region showed an interaction with the ApoE ε4 allele in both populations (Puerto Rican: p-value = 0.019; African American: p-value = 0.005). ApoE ε4 alleles on an African background conferred a lower risk than those with a European ancestral background, regardless of population (Puerto Rican: OR = 1.26 on African background, OR = 4.49 on European; African American: OR = 2.34 on African background, OR = 3.05 on European background). Factors contributing to the lower risk effect in the ApoE gene ε4 allele are likely due to ancestry-specific genetic factors near ApoE rather than non-genetic ethnic, cultural, and environmental factors.
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http://dx.doi.org/10.1371/journal.pgen.1007791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6281216PMC
December 2018

Linkage analysis of multiplex Caribbean Hispanic families loaded for unexplained early-onset cases identifies novel Alzheimer's disease loci.

Alzheimers Dement (Amst) 2018 27;10:554-562. Epub 2018 Aug 27.

The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, USA.

Introduction: Less than 10% of early-onset Alzheimer's disease (EOAD) is explained by known mutations.

Methods: We conducted genetic linkage analysis of 68 well-phenotyped Caribbean Hispanic families without clear inheritance patterns or mutations in , , and and with two or more individuals with EOAD.

Results: We identified 16 (logarithm of odds > 3.6) linked regions, including eight novel loci for EOAD (2p15, 5q14.1, 11p15.1, 13q21.22, 13q33.1, 16p12.1, 20p12.1, and 20q11.21) and eight regions previously associated with late-onset Alzheimer's disease. The strongest signal was observed at 16p12.1 (25 cM, 33 Mb; heterogeneity logarithm of odds = 5.3), ∼3 Mb upstream of the ceroid lipofuscinosis 3 () gene associated with juvenile neuronal ceroid lipofuscinosis (JNCL), which functions in retromer trafficking and has been reported to alter intracellular processing of the amyloid precursor protein.

Discussion: This study supports the notion that the genetic architectures of unexplained EOAD and late-onset AD overlap partially, but not fully.
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http://dx.doi.org/10.1016/j.dadm.2018.07.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6215058PMC
August 2018

Whole exome sequencing study identifies novel rare and common Alzheimer's-Associated variants involved in immune response and transcriptional regulation.

Mol Psychiatry 2020 08 14;25(8):1859-1875. Epub 2018 Aug 14.

McDonnell Genome Institute, Washington University, St. Louis, MO, USA.

The Alzheimer's Disease Sequencing Project (ADSP) undertook whole exome sequencing in 5,740 late-onset Alzheimer disease (AD) cases and 5,096 cognitively normal controls primarily of European ancestry (EA), among whom 218 cases and 177 controls were Caribbean Hispanic (CH). An age-, sex- and APOE based risk score and family history were used to select cases most likely to harbor novel AD risk variants and controls least likely to develop AD by age 85 years. We tested ~1.5 million single nucleotide variants (SNVs) and 50,000 insertion-deletion polymorphisms (indels) for association to AD, using multiple models considering individual variants as well as gene-based tests aggregating rare, predicted functional, and loss of function variants. Sixteen single variants and 19 genes that met criteria for significant or suggestive associations after multiple-testing correction were evaluated for replication in four independent samples; three with whole exome sequencing (2,778 cases, 7,262 controls) and one with genome-wide genotyping imputed to the Haplotype Reference Consortium panel (9,343 cases, 11,527 controls). The top findings in the discovery sample were also followed-up in the ADSP whole-genome sequenced family-based dataset (197 members of 42 EA families and 501 members of 157 CH families). We identified novel and predicted functional genetic variants in genes previously associated with AD. We also detected associations in three novel genes: IGHG3 (p = 9.8 × 10), an immunoglobulin gene whose antibodies interact with β-amyloid, a long non-coding RNA AC099552.4 (p = 1.2 × 10), and a zinc-finger protein ZNF655 (gene-based p = 5.0 × 10). The latter two suggest an important role for transcriptional regulation in AD pathogenesis.
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http://dx.doi.org/10.1038/s41380-018-0112-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6375806PMC
August 2020

Pedigree Selection and Information Content.

Curr Protoc Hum Genet 2018 04;97(1):e56

Department of Biostatistics and Epidemiology, Case Western Reserve University, Cleveland, Ohio.

In this article, we discuss strategies for selection of families and family members for genetic studies. We will evaluate strategies to sample large families with multiply affected members, sibships, and nuclear families. In addition, we have added a section to discuss sub-sampling within pedigrees for large sequencing studies, particularly when genome-wide SNP chips are available on all members of a pedigree. The type of family sampled for a study will determine the statistical analyses and power of discovery of genetic findings. We will evaluate study designs that maximize power and allow for linkage and association analyses to identify genetic loci predisposing to phenotype. © 2018 by John Wiley & Sons, Inc.
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http://dx.doi.org/10.1002/cphg.56DOI Listing
April 2018

Whole genome sequencing of Caribbean Hispanic families with late-onset Alzheimer's disease.

Ann Clin Transl Neurol 2018 Apr 13;5(4):406-417. Epub 2018 Mar 13.

The Taub Institute for Research on Alzheimer's Disease and the Aging Brain New York.

Objective: To identify rare causal variants underlying known loci that segregate with late-onset Alzheimer's disease (LOAD) in multiplex families.

Methods: We analyzed whole genome sequences (WGS) from 351 members of 67 Caribbean Hispanic (CH) families from Dominican Republic and New York multiply affected by LOAD. Members of 67 CH and additional 47 Caucasian families underwent WGS as a part of the Alzheimer's Disease Sequencing Project (ADSP). All members of 67 CH families, an additional 48 CH families and an independent CH case-control cohort were subsequently genotyped for validation. Patients met criteria for LOAD, and controls were determined to be dementia free. We investigated rare variants segregating within families and gene-based associations with disease within LOAD GWAS loci.

Results: A variant in p.R434W, segregated significantly with LOAD in two large families (OR = 5.77, 95% CI: 1.07-30.9, = 0.041). In addition, missense mutations in and under previously reported linkage peaks at 7q14.3 and 11q12.3 segregated completely in one family and in follow-up genotyping both were nominally significant ( < 0.05). We also identified rare variants in a number of genes associated with LOAD in prior genome wide association studies, including ( = 0.049), ( = 0.0098) and ( = 0.040).

Conclusions And Relevance: Rare variants in multiple genes influence the risk of LOAD disease in multiplex families. These results suggest that rare variants may underlie loci identified in genome wide association studies.
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http://dx.doi.org/10.1002/acn3.537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5899906PMC
April 2018
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