Linkage Analysis in Caribbean Hispanic Families with Puerto Rican Ancestry Idenitfies an Alzheimer Disease Locus on chromosome 9

AbstractBackgroundThe ancestral genetic heterogeneity (admixture) of Caribbean Hispanics makes studies of this population critical to the discovery of ancestry-specific genetic factors in Alzheimer disease. In this study, we performed whole genome sequencing in multiplex Caribbean Hispanic Puerto Rican families to identify rare causal variants influencing Alzheimer disease through linkage and segregation-based approaches.MethodsAs part of the Puerto Rican Alzheimer Disease Initiative, whole genome sequencing data were generated for 100 individuals (61 affected) from 23 Puerto Rican families. To identify the genetic loci likely to carry risk variants, we performed a parametric multipoint affected individuals-only linkage analysis using MERLIN software. Following the linkage analysis, we identified the consensus region (heterogeneity logarithm of the odds score (HLOD) > 5.1), annotated variants using Ensembl Variant Effect Predictor, and combined annotation dependent depletion score (CADD). Finally, we prioritized variants according to allele frequency (< 0.01), function (CADD > 10), and complete segregation among affected individuals.ResultsA locus at 9p21 produced a linkage HLOD score of 5.1 in the parametric affecteds-only multipoint affected individuals-only model supported by 9 families. Through the prioritization step, we selected 36 variants (22 genic variants). Candidate genes in the regions include C9orf72, UNC13B, and ELAVL2.ConclusionsLinkage analysis of Caribbean Hispanics Puerto Rican families confirmed previously reported linkage to 9p21 in non-Hispanic White and Israeli-Arap families. Our results suggest several candidates in the region as conferring AD risk. Identified putative damaging rare variants in multiplex families indicates the critical role of rare variation in Alzheimer disease etiology.

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Challenges of Linkage Analysis in the Era of Whole-Genome Sequencing

Genetic Epidemiology ◽

10.1002/gepi.21832 ◽

2014 ◽

Vol 38 (S1) ◽

pp. S92-S96 ◽

Cited By ~ 5

Author(s):

Stephanie A. Santorico ◽

Karen L. Edwards

Keyword(s):

Linkage Analysis ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

Whole Genome

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AFLAP: Assembly-Free Linkage Analysis Pipeline using k-mers from whole genome sequencing data

10.1101/2020.09.14.296525 ◽

2020 ◽

Author(s):

Kyle Fletcher ◽

Lin Zhang ◽

Juliana Gil ◽

Rongkui Han ◽

Keri Cavanaugh ◽

...

Keyword(s):

Linkage Analysis ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

Genetic Map ◽

Genotyping By Sequencing ◽

Genetic Maps ◽

Whole Genome ◽

Sequencing Data ◽

Analysis Pipeline ◽

Genome Assemblies

AbstractBackgroundGenetic maps are an important resource for validation of genome assemblies, trait discovery, and breeding. Next generation sequencing has enabled production of high-density genetic maps constructed with 10,000s of markers. Most current approaches require a genome assembly to identify markers. Our Assembly Free Linkage Analysis Pipeline (AFLAP) removes this requirement by using uniquely segregating k-mers as markers to rapidly construct a genotype table and perform subsequent linkage analysis. This avoids potential biases including preferential read alignment and variant calling.ResultsThe performance of AFLAP was determined in simulations and contrasted to a conventional workflow. We tested AFLAP using 100 F2 individuals of Arabidopsis thaliana, sequenced to low coverage. Genetic maps generated using k-mers contained over 130,000 markers that were concordant with the genomic assembly. The utility of AFLAP was then demonstrated by generating an accurate genetic map using genotyping-by-sequencing data of 235 recombinant inbred lines of Lactuca spp. AFLAP was then applied to 83 F1 individuals of the oomycete Bremia lactucae, sequenced to >5x coverage. The genetic map contained over 90,000 markers ordered in 19 large linkage groups. This genetic map was used to fragment, order, orient, and scaffold the genome, resulting in a much-improved reference assembly.ConclusionsAFLAP can be used to generate high density linkage maps and improve genome assemblies of any organism when a mapping population is available using whole genome sequencing or genotyping-by-sequencing data. Genetic maps produced for B. lactucae were accurately aligned to the genome and guided significant improvements of the reference assembly.

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P2-140: GENOME-WIDE LINKAGE ANALYSIS OF CARIBBEAN HISPANIC PUERTO RICAN FAMILIES SUPPORTS EVIDENCE OF LINKAGE TO C9ORF72 REGION OF CHROMOSOME 9

Alzheimer s & Dementia ◽

10.1016/j.jalz.2019.06.2547 ◽

2019 ◽

Vol 15 ◽

pp. P626-P627

Author(s):

Farid Rajabli ◽

Briseida E. Feliciano-Astacio ◽

Katrina Celis ◽

Kara L. Hamilton-Nelson ◽

Larry D. Adams ◽

...

Keyword(s):

Linkage Analysis ◽

Puerto Rican ◽

Chromosome 9 ◽

Genome Wide ◽

Puerto Rican Families

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Whole-Genome Sequencing Identifies Novel Functional Loci Associated with Lung Function in Puerto Rican Youth

American Journal of Respiratory and Critical Care Medicine ◽

10.1164/rccm.202002-0351oc ◽

2020 ◽

Vol 202 (7) ◽

pp. 962-972

Author(s):

Eunice Y. Lee ◽

Angel C. Y. Mak ◽

Donglei Hu ◽

Satria Sajuthi ◽

Marquitta J. White ◽

...

Keyword(s):

Lung Function ◽

Whole Genome Sequencing ◽

Puerto Rican ◽

Genome Sequencing ◽

Whole Genome

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Impact of whole genome sequencing in Public Health reference laboratories

Microbiology Australia ◽

10.1071/ma17060 ◽

2017 ◽

Vol 38 (4) ◽

pp. 168

Author(s):

Amy V Jennison

Keyword(s):

Public Health ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

Critical Role ◽

Whole Genome ◽

Competitive Price ◽

One Stop ◽

The One ◽

Single Technique

Public Health Microbiology reference laboratories fulfil a critical role in providing overarching testing and surveillance for notifiable, emerging and important pathogens. These duties require the laboratory to possess an extensive repertoire of validated assays and the ability to rapidly respond to novel threats and outbreaks. For these, among other reasons, the ‘one stop shop' approach of whole genome sequencing (WGS) has been embraced by microbiology reference laboratories. The ability to replace multiple labour-intensive assays with a single technique of superior typeability and discrimination at an often competitive price, although not without its challenges, has already begun to change the workflow of Public Health reference laboratories.

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