Ancestry-Dependent Enrichment of Deleterious Homozygotes in Runs of Homozygosity.

Runs of homozygosity (ROH) are important genomic features that manifest when an individual inherits two haplotypes that are identical by descent. Their length distributions are informative about population history, and their genomic locations are useful for mapping recessive loci contributing to both Mendelian and complex disease risk. We have previously shown that ROH, and especially long ROH that are likely the result of recent parental relatedness, are enriched for homozygous deleterious coding variation in a worldwide sample of outbred individuals. However, the distribution of ROH in admixed populations and their relationship to deleterious homozygous genotypes is understudied. Here we analyze whole-genome sequencing data from 1,441 unrelated individuals from self-identified African American, Puerto Rican, and Mexican American populations. These populations are three-way admixed between European, African, and Native American ancestries and provide an opportunity to study the distribution of deleterious alleles partitioned by local ancestry and ROH. We re-capitulate previous findings that long ROH are enriched for deleterious variation genome-wide. We then partition by local ancestry and show that deleterious homozygotes arise at a higher rate when ROH overlap African ancestry segments than when they overlap European or Native American ancestry segments of the genome. These results suggest that, while ROH on any haplotype background are associated with an inflation of deleterious homozygous variation, African haplotype backgrounds may play a particularly important role in the genetic architecture of complex diseases for admixed individuals, highlighting the need for further study of these populations

Population History and Gene Divergence in Native Mexicans Inferred from 76 Human Exomes.

Native American genetic variation remains underrepresented in most catalogs of human genome sequencing data. Previous genotyping efforts have revealed that Mexico's Indigenous population is highly differentiated and substructured, thus potentially harboring higher proportions of private genetic variants of functional and biomedical relevance. Here we have targeted the coding fraction of the genome and characterized its full site frequency spectrum by sequencing 76 exomes from five Indigenous populations across Mexico. Using diffusion approximations, we modeled the demographic history of Indigenous populations from Mexico with northern and southern ethnic groups splitting 7.2 KYA and subsequently diverging locally 6.5 and 5.7 KYA, respectively. Selection scans for positive selection revealed BCL2L13 and KBTBD8 genes as potential candidates for adaptive evolution in Rarámuris and Triquis, respectively. BCL2L13 is highly expressed in skeletal muscle and could be related to physical endurance, a well-known phenotype of the northern Mexico Rarámuri. The KBTBD8 gene has been associated with idiopathic short stature and we found it to be highly differentiated in Triqui, a southern Indigenous group from Oaxaca whose height is extremely low compared to other Native populations

Expression of SMARCD1 interacts with age in association with asthma control on inhaled corticosteroid therapy.

BackgroundGlobal gene expression levels are known to be highly dependent upon gross demographic features including age, yet identification of age-related genomic indicators has yet to be comprehensively undertaken in a disease and treatment-specific context.MethodsWe used gene expression data from CD4+ lymphocytes in the Asthma BioRepository for Integrative Genomic Exploration (Asthma BRIDGE), an open-access collection of subjects participating in genetic studies of asthma with available gene expression data. Replication population participants were Puerto Rico islanders recruited as part of the ongoing Genes environments & Admixture in Latino Americans (GALA II), who provided nasal brushings for transcript sequencing. The main outcome measure was chronic asthma control as derived by questionnaires. Genomic associations were performed using regression of chronic asthma control score on gene expression with age in years as a covariate, including a multiplicative interaction term for gene expression times age.ResultsThe SMARCD1 gene (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 1) interacted with age to influence chronic asthma control on inhaled corticosteroids, with a doubling of expression leading to an increase of 1.3 units of chronic asthma control per year (95% CI [0.86, 1.74], p = 6 × 10- 9), suggesting worsening asthma control with increasing age. This result replicated in GALA II (p = 3.8 × 10- 8). Cellular assays confirmed the role of SMARCD1 in glucocorticoid response in airway epithelial cells.ConclusionFocusing on age-dependent factors may help identify novel indicators of asthma medication response. Age appears to modulate the effect of SMARCD1 on asthma control with inhaled corticosteroids

Ancestry-related assortative mating in Latino populations

Examination of ancestry-informative genetic markers shows that Puerto Rican and Mexican populations have shown strong assortative mating that continues to this day

Identification of CFTR variants in Latino patients with cystic fibrosis from the Dominican Republic and Puerto Rico

BackgroundIn cystic fibrosis (CF), the spectrum and frequency of CFTR variants differ by geography and race/ethnicity. CFTR variants in White patients are wellâ described compared with Latino patients. No studies of CFTR variants have been done in patients with CF in the Dominican Republic or Puerto Rico.MethodsCFTR was sequenced in 61 Dominican Republican patients and 21 Puerto Rican patients with CF and greater than â â â â 60â mmol/L sweat chloride. The spectrum of CFTR variants was identified and the proportion of patients with 0, 1, or 2 CFTR variants identified was determined. The functional effects of identified CFTR variants were investigated using clinical annotation databases and computational prediction tools.ResultsOur study found 10% of Dominican patients had two CFTR variants identified compared with 81% of Puerto Rican patients. No CFTR variants were identified in 69% of Dominican patients and 10% of Puerto Rican patients. In Dominican patients, there were 19 identified CFTR variants, accounting for 25 out of 122 disease alleles (20%). In Puerto Rican patients, there were 16 identified CFTR variants, accounting for 36 out of 42 disease alleles (86%) in Puerto Rican patients. Thirty CFTR variants were identified overall. The most frequent variants for Dominican patients were p.Phe508del and p.Ala559Thr and for Puerto Rican patients were p.Phe508del, p.Arg1066Cys, p.Arg334Trp, and p.I507del.ConclusionsIn this first description of the CFTR variants in patients with CF from the Dominican Republic and Puerto Rico, there was a low detection rate of two CFTR variants after full sequencing with the majority of patients from the Dominican Republic without identified variants.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153634/1/ppul24549.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/153634/2/ppul24549_am.pd

Whole-Genome Sequencing of Individuals from a Founder Population Identifies Candidate Genes for Asthma

Asthma is a complex genetic disease caused by a combination of genetic and environmental risk factors. We sought to test classes of genetic variants largely missed by genome-wide association studies (GWAS), including copy number variants (CNVs) and low-frequency variants, by performing whole-genome sequencing (WGS) on 16 individuals from asthma-enriched and asthma-depleted families. The samples were obtained from an extended 13-generation Hutterite pedigree with reduced genetic heterogeneity due to a small founding gene pool and reduced environmental heterogeneity as a result of a communal lifestyle. We sequenced each individual to an average depth of 13-fold, generated a comprehensive catalog of genetic variants, and tested the most severe mutations for association with asthma. We identified and validated 1960 CNVs, 19 nonsense or splice-site single nucleotide variants (SNVs), and 18 insertions or deletions that were out of frame. As follow-up, we performed targeted sequencing of 16 genes in 837 cases and 540 controls of Puerto Rican ancestry and found that controls carry a significantly higher burden of mutations in IL27RA (2.0% of controls; 0.23% of cases; nominal p = 0.004; Bonferroni p = 0.21). We also genotyped 593 CNVs in 1199 Hutterite individuals. We identified a nominally significant association (p = 0.03; Odds ratio (OR) = 3.13) between a 6 kbp deletion in an intron of NEDD4L and increased risk of asthma. We genotyped this deletion in an additional 4787 non-Hutterite individuals (nominal p = 0.056; OR = 1.69). NEDD4L is expressed in bronchial epithelial cells, and conditional knockout of this gene in the lung in mice leads to severe inflammation and mucus accumulation. Our study represents one of the early instances of applying WGS to complex disease with a large environmental component and demonstrates how WGS can identify risk variants, including CNVs and low-frequency variants, largely untested in GWAS

COMT Val 158 Met polymorphism is associated with post-traumatic stress disorder and functional outcome following mild traumatic brain injury

Mild traumatic brain injury (mTBI) results in variable clinical trajectories and outcomes. The source of variability remains unclear, but may involve genetic variations, such as single nucleotide polymorphisms (SNPs). A SNP in catechol-o-methyltransferase (COMT) is suggested to influence development of post-traumatic stress disorder (PTSD), but its role in TBI remains unclear. Here, we utilize the Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot (TRACK-TBI Pilot) study to investigate whether the COMT Val158Met polymorphism is associated with PTSD and global functional outcome as measured by the PTSD Checklist - Civilian Version and Glasgow Outcome Scale Extended (GOSE), respectively. Results in 93 predominately Caucasian subjects with mTBI show that the COMT Met158 allele is associated with lower incidence of PTSD (univariate odds ratio (OR) of 0.25, 95% CI [0.09-0.69]) and higher GOSE scores (univariate OR 2.87, 95% CI [1.20-6.86]) 6-months following injury. The COMT Val158Met genotype and PTSD association persists after controlling for race (multivariable OR of 0.29, 95% CI [0.10-0.83]) and pre-existing psychiatric disorders/substance abuse (multivariable OR of 0.32, 95% CI [0.11-0.97]). PTSD emerged as a strong predictor of poorer outcome on GOSE (multivariable OR 0.09, 95% CI [0.03-0.26]), which persists after controlling for age, GCS, and race. When accounting for PTSD in multivariable analysis, the association of COMT genotype and GOSE did not remain significant (multivariable OR 1.73, 95% CI [0.69-4.35]). Whether COMT genotype indirectly influences global functional outcome through PTSD remains to be determined and larger studies in more diverse populations are needed to confirm these findings

Reconstructing the Population Genetic History of the Caribbean

The Caribbean basin is home to some of the most complex interactions in recent history among previously diverged human populations. Here, by making use of genome-wide SNP array data, we characterize ancestral components of Caribbean populations on a sub-continental level and unveil fine-scale patterns of population structure distinguishing insular from mainland Caribbean populations as well as from other Hispanic/Latino groups. We provide genetic evidence for an inland South American origin of the Native American component in island populations and for extensive pre-Columbian gene flow across the Caribbean basin. The Caribbean-derived European component shows significant differentiation from parental Iberian populations, presumably as a result of founder effects during the colonization of the New World. Based on demographic models, we reconstruct the complex population history of the Caribbean since the onset of continental admixture. We find that insular populations are best modeled as mixtures absorbing two pulses of African migrants, coinciding with early and maximum activity stages of the transatlantic slave trade. These two pulses appear to have originated in different regions within West Africa, imprinting two distinguishable signatures in present day Afro-Caribbean genomes and shedding light on the genetic impact of the dynamics occurring during the slave trade in the Caribbean.Comment: 26 pages, 6 figures, and supporting informatio

COMT Val 158 Met polymorphism is associated with nonverbal cognition following mild traumatic brain injury

Mild traumatic brain injury (mTBI) results in variable clinical outcomes, which may be influenced by genetic variation. A single-nucleotide polymorphism in catechol-o-methyltransferase (COMT), an enzyme which degrades catecholamine neurotransmitters, may influence cognitive deficits following moderate and/or severe head trauma. However, this has been disputed, and its role in mTBI has not been studied. Here, we utilize the Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot (TRACK-TBI Pilot) study to investigate whether the COMT Val (158) Met polymorphism influences outcome on a cognitive battery 6 months following mTBI--Wechsler Adult Intelligence Test Processing Speed Index Composite Score (WAIS-PSI), Trail Making Test (TMT) Trail B minus Trail A time, and California Verbal Learning Test, Second Edition Trial 1-5 Standard Score (CVLT-II). All patients had an emergency department Glasgow Coma Scale (GCS) of 13-15, no acute intracranial pathology on head CT, and no polytrauma as defined by an Abbreviated Injury Scale (AIS) score of ≥3 in any extracranial region. Results in 100 subjects aged 40.9 (SD 15.2) years (COMT Met (158) /Met (158) 29 %, Met (158) /Val (158) 47 %, Val (158) /Val (158) 24 %) show that the COMT Met (158) allele (mean 101.6 ± SE 2.1) associates with higher nonverbal processing speed on the WAIS-PSI when compared to Val (158) /Val (158) homozygotes (93.8 ± SE 3.0) after controlling for demographics and injury severity (mean increase 7.9 points, 95 % CI [1.4 to 14.3], p = 0.017). The COMT Val (158) Met polymorphism did not associate with mental flexibility on the TMT or with verbal learning on the CVLT-II. Hence, COMT Val (158) Met may preferentially modulate nonverbal cognition following uncomplicated mTBI.Registry: ClinicalTrials.gov Identifier NCT01565551