Background: A key strategy to reduce unintended adolescent pregnancies is to expand access to long-acting reversible contraceptive (LARC) methods, including intrauterine devices and subdermal ...contraceptive implants. LARC services can be provided to adolescents in school-based health and other primary care settings, yet limited knowledge and negative attitudes about LARC methods may influence adolescents’ utilization of these methods. This study aimed to evaluate correlates of knowledge and acceptability of LARC methods among adolescent women at a school-based health center (SBHC). Methods: In this cross-sectional study, female patients receiving care at 2 SBHCs in Seattle, Washington completed an electronic survey about sexual and reproductive health. Primary outcomes were (1) LARC knowledge as measured by percentage correct of 10 true-false questions and (2) LARC acceptability as measured by participants reporting either liking the idea of having an intrauterine device (IUD)/subdermal implant or currently using one. Results: A total of 102 students diverse in race/ethnicity and socioeconomic backgrounds completed the survey (mean age 16.2 years, range 14.4-19.1 years). Approximately half reported a lifetime history of vaginal sex. Greater LARC knowledge was associated with white race (regression coefficient coef = 26.8; 95% CI 13.3-40.4; P < .001), history of vaginal intercourse (coef = 29.9; 95% CI 17.1-42.7; P < .001), and current/prior LARC use (coef = 22.8; 95% CI 6.5-40.0; P = .007). Older age was associated with lower IUD acceptability (odds ratio = 0.53, 95% CI 0.30-0.94; P = .029) while history of intercourse was associated with greater implant acceptability (odds ratio 5.66, 95% CI 1.46-22.0; P = .012). Discussion: Adolescent women in this SBHC setting had variable knowledge and acceptability of LARC. A history of vaginal intercourse was the strongest predictor of LARC acceptability. Our findings suggest a need for LARC counseling and education strategies, particularly for young women from diverse cultural backgrounds and those with less sexual experience.
Investigative genetic genealogy (IGG) has emerged as a highly effective tool for tying a forensic DNA sample to an identity. While much of the attention paid to IGG has focused on cases where the DNA ...is from an unknown suspect, IGG has also been used to help close hundreds of unidentified human remains (UHR) cases. Genome-wide single-nucleotide polymorphism (SNP) genotype data can be obtained from forensic samples using microarray genotyping or whole-genome sequencing (WGS) with protocols optimized for degraded DNA. After bioinformatic processing, the SNP data can be uploaded to public GG databases that allow law enforcement usage, where it can be compared with other users' data to find distant relatives. A genetic genealogist can then build the family trees of the relatives to narrow down the identity of the source of the forensic DNA sample. To date, 367 UHR identifications using IGG have been publicly announced. The same IGG techniques developed and refined for UHR cases have significant potential for disaster victim identification, where DNA is often extremely compromised, and close family references may not be available. This paper reviews the laboratory, bioinformatic, and genealogical techniques used in IGG for UHR cases and presents three case studies that demonstrate how IGG is assisting with remains identification.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease in which microglia play a significant and active role. Recently, a rare missense variant (p.R47H) in the microglial activating ...gene TREM2 was found to increase the risk of several neurodegenerative diseases, including Alzheimer disease. Whether the p.R47H variant is a risk factor for ALS is not known.
To determine whether p.R47H (rs75932628) in TREM2 is a risk factor for ALS and assess whether TREM2 expression is dysregulated in disease.
Samples of DNA from 923 individuals with sporadic ALS and 1854 healthy control individuals self-reported as non-Hispanic white were collected from ALS clinics in the United States and genotyped for the p.R47H variant in TREM2. Clinical data were obtained on ALS participants for genotype/phenotype correlations. Expression of TREM2 was measured by quantitative polymerase chain reaction and compared in spinal cord samples from 18 autopsied patients with ALS and 12 neurologically healthy controls, as well as from wild-type and transgenic SOD1G93A mice.
Minor allele frequency of rs75932628 and relative expression of TREM2.
The TREM2 variant p.R47H was more common in patients with ALS than in the controls and is therefore a significant risk factor for ALS (odds ratio, 2.40; 95% CI, 1.29-4.15; P = 4.1×10-3). Furthermore, TREM2 expression was increased in spinal cord samples from ALS patients and SOD1G93A mice (P = 2.8×10-4 and P = 2.8×10-9, respectively), confirming dysregulated TREM2 in disease. Expression of TREM2 in the human spinal cord was negatively correlated with survival (P = .04) but not with other phenotypic aspects of disease.
This study demonstrates that the TREM2 p.R47H variant is a potent risk factor for sporadic ALS. To our knowledge, these findings identify the first genetic influence on neuroinflammation in ALS and highlight the TREM2 signaling pathway as a therapeutic target in ALS and other neurodegenerative diseases.
Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease with no effective treatment. We report the results of a moderate-scale sequencing study aimed at increasing the number of ...genes known to contribute to predisposition for ALS. We performed whole-exome sequencing of 2869 ALS patients and 6405 controls. Several known ALS genes were found to be associated, and TBK1 (the gene encoding TANK-binding kinase 1) was identified as an ALS gene. TBK1 is known to bind to and phosphorylate a number of proteins involved in innate immunity and autophagy, including optineurin (OPTN) and p62 (SQSTM1/sequestosome), both of which have also been implicated in ALS. These observations reveal a key role of the autophagic pathway in ALS and suggest specific targets for therapeutic intervention.
DNA-assisted identification of historical remains requires the genetic analysis of highly degraded DNA, along with a comparison to DNA from known relatives. This can be achieved by targeting single ...nucleotide polymorphisms (SNPs) using a hybridization capture and next-generation sequencing approach suitable for degraded skeletal samples. In the present study, two SNP capture panels were designed to target ~ 25,000 (25 K) and ~ 95,000 (95 K) nuclear SNPs, respectively, to enable distant kinship estimation (up to 4th degree relatives). Low-coverage SNP data were successfully recovered from 14 skeletal elements 75 years postmortem using an Illumina MiSeq benchtop sequencer. All samples contained degraded DNA but were of varying quality with mean fragment lengths ranging from 32 bp to 170 bp across the 14 samples. SNP comparison with DNA from known family references was performed in the Parabon Fx Forensic Analysis Platform, which utilizes a likelihood approach for kinship prediction that was optimized for low-coverage sequencing data with cytosine deamination. The 25 K panel produced 15,000 SNPs on average, which allowed for accurate kinship prediction with strong statistical support in 16 of the 21 pairwise comparisons. The 95 K panel increased the average SNPs to 42,000 and resulted in an additional accurate kinship prediction with strong statistical support (17 of 21 pairwise comparisons). This study demonstrates that SNP capture combined with massively parallel sequencing on a benchtop platform can yield sufficient SNP recovery from compromised samples, enabling accurate, extended kinship predictions.
•Hybridization capture facilitated recovery of thousands of nuclear SNPs from historical remains.•A genotype likelihood approach was utilized for SNP profiling of degraded DNA.•Family reference samples were genotyped using a standard SNP microarray.•The Parabon Fχ Forensic Analysis Platform enabled distant kinship estimation.
In 2018, the Oregon State Medical Examiner’s Office (OSME) received a grant from the Bureau of Justice Assistance to use investigative genetic genealogy (IGG) with Parabon NanoLabs (Parabon) to ...attempt to make identifications in their unidentified human remains cases. Samples were screened for DNA quantity and quality, and selected samples were sent for genome-wide single nucleotide polymorphism (SNP) generation. This multi-year collaboration has been extraordinarily successful: of 43 cases submitted, 39 cases have been investigated using IGG, and 30 have resulted in an identification so far.
Abstract Hexanucleotide repeat expansions in C9ORF72 are a common cause of familial and apparently sporadic amyotrophic lateral sclerosis (ALS) and frontal temporal dementia (FTD). The mechanism by ...which expansions cause neurodegeneration is unknown, but current evidence supports both loss-of-function and gain-of-function mechanisms. We used pooled next-generation sequencing of the C9ORF72 gene in 389 ALS patients to look for traditional loss-of-function mutations. Although rare variants were identified, none were likely to be pathogenic, suggesting that mutations other than the repeat expansion are not a common cause of ALS, and providing supportive evidence for a gain-of-function mechanism. We also show by repeat-primed PCR genotyping that the C9ORF72 expansion frequency varies by geographical region within the United States, with an unexpectedly high frequency in the Mid-West. Finally we also show evidence of somatic instability of the expansion size by Southern blot, with the largest expansions occurring in brain tissue.
Clubfoot is a common musculoskeletal birth defect for which few causative genes have been identified. To identify the genes responsible for isolated clubfoot, we screened for genomic copy-number ...variants with the Affymetrix Genome-wide Human SNP Array 6.0. A recurrent chromosome 17q23.1q23.2 microduplication was identified in 3 of 66 probands with familial isolated clubfoot. The chromosome 17q23.1q23.2 microduplication segregated with autosomal-dominant clubfoot in all three families but with reduced penetrance. Mild short stature was common and one female had developmental hip dysplasia. Subtle skeletal abnormalities consisted of broad and shortened metatarsals and calcanei, small distal tibial epiphyses, and thickened ischia. Several skeletal features were opposite to those described in the reciprocal chromosome 17q23.1q23.2 microdeletion syndrome associated with developmental delay and cardiac and limb abnormalities. Of note, during our study, we also identified a microdeletion at the locus in a sibling pair with isolated clubfoot. The chromosome 17q23.1q23.2 region contains the T-box transcription factor TBX4, a likely target of the bicoid-related transcription factor PITX1 previously implicated in clubfoot etiology. Our result suggests that this chromosome 17q23.1q23.2 microduplication is a relatively common cause of familial isolated clubfoot and provides strong evidence linking clubfoot etiology to abnormal early limb development.
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