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A collection of recent Amish and plain Anabaptist studies research publications: Genetics, 2021-2022

Anna Spector, Abhishek Wadhawan, Niel Constantine, Kathy Ryan, Iqra Mohyuddin, Aline Dagdag, Lisa Brenner, Melanie Daue, Robert Schifferle, Robert Ernst, Braxton Mitchell, Mark Reynolds, Teodor Postolache. (2021). 136 Sleep and Porphyromonas gingivalis K-Capsular IgG Serotypes: A Study in the Old Order Amish. Sleep, 44(2), A55–A56.

Abstract: Sleep problems and periodontal disease have a bidirectional relationship and are independently linked with depression, dementia, and metabolic disease. Inadequate sleep can worsen inflammation, a hallmark of periodontal disease, and the activation of the immune system can alter sleep/wake cycles. A key player in periodontal disease is Porphyromonas gingivalis, a bacteria that can translocate to the brain and induce miRNA’s. Antibodies to P. gingivalis capsular virulence factors, K1-7, have been used to estimate P. gingivalis virulence. This study was conducted to explore cross-sectional associations between seropositivity of K serotypes of P. gingivalis and measures of self-reported impairment in sleep. If identified, these links would provide a rationale to initiate causality and mediation studies. We hypothesized that sleep impairment is positively associated with P. gingivalis K IgG serointensity. Key words: inflammation, immune system, metabolic disease, periodontal disease, porphyromonas gingivalis, sleep, sleep/wake cycle, dementia, depression

Boris Tizenberg, Anna Spector, Abhishek Wadhawan, Soren Snitker, Mark Reynolds, Teodore, Postolache. (2021). Association Between Problems During Daytime Due to Poor Sleep and Indicators of Poor Dental Health: A Study in the Old Order Amish. Biological Psychology 89(9):S314-S315.

Abstract: Periodontal disease, a modifiable contributor to inflammation, mediates associations with morbidity and mortality of cardiovascular, metabolic, and perhaps, psychiatric disorders. Predictive associations of sleep problems with psychiatric and metabolic disorders have been described, and links between periodontal disease and sleep problems have surfaced. Hence, we examined links between measures of sleep-related problems and surrogate variables of periodontitis. To reduce confounding, we performed our study in the Old Order Amish (OOA), who have a low prevalence of smoking. Key words: periodontal disease, inflammation, metabolic disease, sleep

Muneeswar Gupta Nittala; Jyotsna Maram; Federico Covi; Swetha Bindu Velaga; Jonathan L Haines; Margaret A Pericak-Vance; Dwight Stambolian; Srinivas R Sadda. (2021). ARVO Annual Meeting Abstract: Risk Factors for Progression of Age-Related Macular Degeneration: Amish Eye Study. Investigative Ophthalmology & Visual Science. 62(8): 102

Abstract: Purpose: To evaluate optical coherence tomography (OCT)-based risk factors for progression to late Age-related macular degeneration (AMD) in a population-based of the elderly Amish. Methods: A total of 1339 subjects (2668 eyes) were enrolled in this multicenter, prospective, longitudinal, observational study as part of the population-based Amish eye study. 666 subjects (49.7%) returned for a two-year follow-up visit and underwent complete ophthalmic exam, OCT (Spectralis 20°X20°), infrared reflectance images (IR) & olor fundus photography. Baseline OCT images were reviewed for presence of drusen volume > 0.03 mm3 in the central 3mm ring, intraretinal hyperreflective foci (IHRF), hyporeflective drusen core (hDC), subretinal drusenoid deposits (SDD), drusenoid pigment epithelium detachment (PED), subfoveal choroidal thickness, drusen area, volume within 3, 5-mm circles centered on ovea. Presence of SDD/reticular pseudodrusen (RPD) were also evaluated on IR images, including in regions outside the OCT scan field. Two year follow-up images were evaluated for presence of late AMD (geographic atrophy/macular neovascularization). These features at baseline were correlated with 2-year incidence of late AMD development by logistic regression. Results: Twenty-one (1.5%) of 1332 eyes progressed to late AMD at 2 years. Mean age of study subjects was 65±10.17 (±SD) years and 410 were female. Univariate logistic regression showed drusen area, volume in 3 & 5-mm circles, subfoveal choroidal thickness, drusen volume ≥ 0.03 mm3 in 3-mm ring, SDD, IHRF, and hDC were all associated with an increased risk for development of late AMD (odds ratios (OR) and 95% confidence intervals shown in table 1). Multivariate regression model identified that drusen volume in the 3-mm circle (OR:2.59, p=0.049) & presence of IHRF (OR:57.06, p<0.001) remained as independent and significant risk factors for progression to late AMD. Conclusions: This population-based study confirms previous findings from clinic-based studies that high central drusen volume and IHRF are associated with an increased risk of progression to late AMD. These findings may of value in risk stratifying patients in clinical practice or identifying subjects for early intervention clinical trials. Key words: age-related macular degeneration, drusen, intraretinal hyperreflective foci

Ayesha Nuri Karamat; Sowmya Srinivas; Muneeswar Nittala; Swetha Velaga; Jonathan L Haines; Dwight Stambolian; Srinivas R Sadda. (2021). ARVO Annual Meeting Abstract: Sensitivity and Specificity of Reticular Pseudodrusen detection using multimodal imaging in Amish Population. Investigative Ophthalmology & Visual Science. 62(8): 450.

Abstract: Purpose: To compare sensitivity and specificity for the detection of reticular pseudodrusen (RPD) associated with age-related macular degeneration using multiple imaging modalities. Methods: A post-hoc analysis was performed on images collected from a family-based prospective cohort study of 1320 elderly Amish subjects (age range 50–99 years) (2,640 eyes) who had a family history of at least 1 individual with AMD. All subjects underwent complete ophthalmic examination, spectral domain optical coherence tomography (SDOCT; 6x6mm ~ 20o), blue-light fundus autofluorescence (FAF), infrared reflectance (IR), and flash color fundus photography (CFP). Both eyes were included in this analysis. Individual imaging modalities were assessed separately in a masked fashion by expert human graders for the presence of RPD, also termed subretinal drusenoid deposits (SDD). To be deemed to be present, a minimum of three discrete lesions were required. Ground truth was established based on the presence of RPD on at least two modalities. Sensitivity and specificity were computed for each individual modality against the ground truth. As SDOCT images covered a smaller region (20o vs 30o) compared to other imaging analyses, SDOCT sensitivity and specificity was recomputed after cropping the other modalities to a similar region of interest. Results: RPD were noted to be present on at least one modality in 140 (6.3%) of the 2640 eyes, and in 132 eyes (of 66 subjects; 5%) they were noted in at least two modalities (ground truth or reference determination). Overall, RPD were observed in 133 (5 %), 126 (4.8%), 115 (4.4%), 35 (1.3 %) eyes by IR, FAF, SDOCT and CFP respectively. Sensitivity and specificity for identification of RPD for each imaging modality is shown in Table 1. IR demonstrated the highest sensitivity, and CFP showed the lowest sensitivity. When cropping to a similar region, sensitivity and specificity of SDOCT improved to 93% and 95%, respectively. Conclusions: IR imaging appears to be the most sensitive modality for detection of RPD, with a high specificity. SDOCT imaging can also show high sensitivity but may require the scan field to be enlarged beyond the dimensions commonly acquired in clinical practice. Key words: reticular pseudodrusen, age-related macular degeneration, IR imaging, SDOCT

Michael David Osterman; Yeunjoo E Song; Muneeswar Nittala; Srinivas R Sadda; William K Scott; Dwight Stambolian; Margaret A Pericak-Vance; Jonathan L Haines. (2021). ARVO Annual Meeting Abstract: Investigation of the use of drusen as a biomarker for age-related macular degeneration reveals shared genetic risk in the Amish. Investigative Ophthalmology & Visual Science. 62(8):170.

Abstract: Purpose: Age-related macular degeneration (AMD) is the leading cause of vision loss nationwide and accounts for 8.7% of blindness. Detailed GA and drusen measurements may be promising biomarkers for staging and monitoring of AMD. However, the genetic relationship between these traits and AMD is not fully understood. Here, we investigate the genetics of quantitative measures of drusen and GA in an Amish population using genetic risk scores (GRSs) derived from a previous large AMD genome-wide association study (GWAS). Methods: We performed chip genotyping using an Illumina Multi-Ethnic Genotyping Array with custom content. GA and drusen measures were obtained from macular optical coherence tomography (OCT) volume scans. 1,117 Amish adults with a family history of AMD from Ohio, Pennsylvania, and Indiana were included in the analyses after quality control and assurance. GRS were constructed using summary statistics of genome-wide significant SNPs for AMD from Fritsche et al. (2016). We tested the impact of the GRS for both the presence/absence of GA and drusen and, for those with GA and/or drusen, the impact on the measures. Traits included geographic atrophy, drusen area, and drusen volume within 3 and 5mm circles centered on the fovea. Logistic regression models were used to test the added utility in predicting the presence each of these drusen traits beyond a basic covariate-only model including age, sex, and smoking status. Similarly, linear models were constructed to investigate prediction of the quantitative measures of each of these traits by using the same predictors on subsets of individuals with presence of each of the traits. Results: Results indicated a small, but statistically significant (p < 0.05), effect of the GRS to improve model performance for presence of each of the five traits. Area under curve (AUC) for drusen area and volume in a 3mm circle improved from 0.797 and 0.831 to 0.825 and 0.864, respectively, by adding the GRS to a covariate-only model. Further, it had a significant effect in improving prediction of the quantitative measures of drusen area and volume. Conclusions: These results suggest that drusen development and AMD share underlying risk loci, helping to elucidate the relationship between drusen and AMD, potentially allowing for future use of drusen traits as a biomarker. Key words: age-related macular degeneration, drusen, genetics

Swetha Bindu Velaga; Gagan Singh; Muneeswar Nittala; Dwight Stambolian; Margaret A Pericak-Vance; Jonathan L Haines; Srinivas R Sadda. (2021). ARVO Annual Meeting Abstract: Alterations of the Ganglion Cell Complex in Age-Related Macular Degeneration: an AMISH Eye Study Analysis. Investigative Ophthalmology & Visual Science. 62(8):103.

Abstract: Purpose: Although the outer retina is the primary area affected in age-related macular degeneration (AMD), secondary alterations in the inner retina have been suggested. To test this hypothesis, we evaluated the Ganglion Cell Complex (GCC) thickness in subjects with AMD. Methods: A total of 620 eyes of 310 elderly (>age 50) Amish individuals who were enrolled in a population-based study were included in this post-hoc analysis. All subjects underwent complete ophthalmic examination, optical coherence tomography (Cirrus OCT, 6x6mm, 512 x 128) and flash color fundus photography. Foveal central subfield retinal thickness, mean retinal thickness, mean macular volume, and mean thickness of the GCC were obtained using the instrument software. The color fundus images were graded according to the Beckman classification as: Stage 0 (normal), Stage 1 (normal aging), Stage 2 (early AMD), Stage 3 (intermediate AMD), and Stage 4 (late AMD). The GCC thickness between groups were compared in a pairwise fashion using t tests. Results: Among the 620 eyes, 408 eyes were normal, 67 eyes had early AMD, 101 eyes had intermediate AMD, and 44 eyes had late AMD. The mean age was significantly (<0.0001) lower in the normal group (62.43 years) compared to the AMD group as a whole (71.88 years). After adjusting for age, there was no significant difference in retinal thickness (p = 0.16) or retinal volume (p = 0.14) between the study groups. However, the mean GCC thickness was significantly (p < 0.05) lower in all AMD groups [early AMD: 73.94µm; intermediate AMD: 76.55µm; late AMD: 58.80µm] compared to normals (78.22 microns). Conclusions: Eyes with AMD show lower GCC thickness compared to normal eyes, with the most severe reduction observed in eyes with late AMD. Alterations in the inner retina during the progression of AMD warrant further study. Key Words: age-related macular degeneration, ganglion cell complex thickness

Andrea R. Waksmunski; Kristy Miskimen; Yeunjoo E. Song; Michelle Grunin; Renee Laux; Denise Fuzzell; Sarada Fuzzell; Larry D. Adams; Laura Caywood; Michael Prough; Dwight Stambolian; William K. Scott; Margaret A. Pericak-Vance; Jonathan L. Haines. (2022). Consequences of a Rare Complement Factor H Variant for Age-Related Macular Degeneration in the Amish. Investigative Ophthalmology & Visual Science, 63(9):8.

Abstract: Purpose: Genetic variants in the complement factor H gene (CFH) have been consistently implicated in age-related macular degeneration (AMD) risk. However, their functional effects are not fully characterized. We previously identified a rare, AMD-associated variant in CFH (P503A, rs570523689) in 19 Amish individuals, but its functional consequences were not investigated. Methods: We performed genotyping for CFH P503A in 1326 Amish individuals to identify additional risk allele carriers. We examined differences for age at AMD diagnosis between carriers and noncarriers. In blood samples from risk allele carriers and noncarriers, we quantified (i) CFH RNA expression, (ii) CFH protein expression, and (iii) C-reactive protein (CRP) expression. Potential changes to the CFH protein structure were interrogated computationally with Phyre2 and Chimera software programs. Results: We identified 39 additional carriers from Amish communities in Ohio and Indiana. On average, carriers were younger than noncarriers at AMD diagnosis, but this difference was not significant. CFH transcript and protein levels in blood samples from Amish carriers and noncarriers were also not significantly different. CRP levels were also comparable in plasma samples from carriers and noncarriers. Computational protein modeling showed slight changes in the CFH protein conformation that were predicted to alter interactions between the CFH 503 residue and other neighboring residues. Conclusions: In total, we have identified 58 risk allele carriers for CFH P503A in the Ohio and Indiana Amish. Although we did not detect significant differences in age at AMD diagnosis or expression levels of CFH in blood samples from carriers and noncarriers, we observed modest structural changes to the CFH protein through in silico modeling. Based on our functional and computational observations, we hypothesize that CFH P503A may affect CFH binding or function rather than expression, which would require additional research to confirm. Key words: age-related macular degeneration, complement factor H gene, CFH protein, CFH P503A

Wallace SE, Bean LJH. Resources for Genetics Professionals — Genetic Disorders Associated with Founder Variants Common in the Hutterite Population. 2020 May 7 [Updated 2022 Dec 1]. In: Adam MP, Everman DB, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023.

A founder variant is a pathogenic variant observed at high frequency in a specific population due to the presence of the variant in a single ancestor or small number of ancestors. The presence of a founder variant can affect the approach to molecular genetic testing. When one or more founder variants account for a large percentage of all pathogenic variants found in a population, testing for the founder variant(s) may be performed first. The table below includes common founder variants – here defined as three or fewer variants that account for more than 50% of the pathogenic variants identified in a single gene in individuals of a specific ancestry – in individuals of Hutterite ancestry. Note: Pathogenic variants that are common worldwide due to a DNA sequence hot spot are not considered founder variants and thus are not included.

Sarah Ehrenberg, Catherine Walsh Vockley, Paige Heiman, Zineb Ammous, Olivia Wenger, Jerry Vockley, Lina Ghaloul-Gonzalez. (2022). Natural history of propionic acidemia in the Amish population. Molecular Genetics and Metabolism Reports, 5;33:100936.

Abstract: Propionic acidemia (PA) in the Amish is caused by a homozygous pathogenic variant (c.1606A>G; p.Asn536Asp) in the PCCB gene. Amish patients can have borderline or normal newborn screening (NBS) results and symptoms can present at any time from early childhood to mid-adulthood. Early diagnosis and initiation of treatment for PA in the non-Amish population improves patient outcomes. Here, we present data from a retrospective chart review of Amish patients diagnosed with PA from three different medical centers in order to document its natural history in the Amish and determine the influence of treatment on outcomes in this population. A total of 38 patients with average current age 19.9 years (range 4y-45y), 57.9% males, were enrolled in the study. Fourteen patients (36.8%) were diagnosed with a positive newborn screening (NBS) while 24 patients (63.2%) had negative or inconclusive NBS or had no record of NBS in their charts. These 24 patients were diagnosed by screening after a family member was diagnosed with PA (14; 58.3%), following a hospitalization for metabolic acidosis (5; 20.8%), hospitalization for seizures (3; 12.5%) or via cord blood (2; 8.3%). The majority of patients were prescribed a protein restricted diet (32; 84.2%), including metabolic formula (29; 76.3%). Most were treated with carnitine (35; 92.1%), biotin (2; 76.3%) and/or Coenzyme Q10 (16; 42.1%). However, treatment adherence varied widely among patients, with 7 (24.1%) of the patients prescribed metabolic formula reportedly nonadherent. Cardiomyopathy was the most prevalent finding (22; 63.2%), followed by developmental delay/intellectual disability (15; 39.5%), long QT (14; 36.8%), seizures (12; 31.6%), failure to thrive (4; 10.5%), and basal ganglia strokes (3; 7.9%). No difference in outcome was obvious for those diagnosed by NBS and treated early with dietary and supplement management, especially for cardiomyopathy. However, this is a limited retrospective observational study. A prospective study with strict documentation of treatment adherence and universal screening for cardiomyopathy and long QT should be conducted to better study the impact of early detection and treatment. Additional treatment options such as liver transplantation and future therapies such as mRNA or gene therapy should be explored in this population. Key words: Propionic Acidemia; Amish; Newborn screen; Treatment; Cardiomyopathy; Seizures

Choe, Jayme Hyowon. (2022). Associations of Rare Variants Underlying Depressive Symptoms in the Old Order Amish Founder Population. [Master’s Thesis: University of Maryland Baltimore].

Abstract: Depressive disorders are among the leading causes of disability worldwide. Genome-wide association studies of common variants of depressive disorders have identified 178 risk loci, yet mechanisms remain elusive due to the very small effects of common variants. Certain rare variants may have larger effects, but exome and genome sequencing studies to date have been underpowered to detect effects of specific rare variants. One approach to address these limitations is to utilize population isolates, like the Old Order Amish (OOA), in which certain rare variants become enriched due to the population bottleneck effect. This study aimed to identify rare variants associated with depressive symptoms, utilizing whole exome sequencing (WES) and phenotypic data from two OOA cohorts (N = 5,052), the Amish Wellness Study and the Amish Connectome Project. We identified five significant SNP-depressive symptoms associations. Case-series phenotyping revealed high depressive symptoms screening scores across carriers of each variant compared to non-carriers. Key words: Depression, Amish, Genetics, Anhedonia


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A collection of recent Amish and plain Anabaptist studies research publications in healthcare. Cory Anderson & Lindsey Potts (2022). Physical health conditions of the Amish and intervening social mech

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