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[OPEN ACCESS SAMPLE] Recent Research: Genetics (1 of 2), 2021-2022

Updated: Jun 26, 2023

Seppo, A. E., Bu, K., Jumabaeva, M., Thakar, J., Choudhury, R. A., Yonemitsu, C., Bode, L., Martina, C. A., Allen, M., Tamburini, S., Piras, E., Wallach, D. S., Looney, R. J., Clemente, J. C., & Järvinen, K. M. (2021). Infant gut microbiome is enriched with Bifidobacterium longum ssp. infantis in Old Order Mennonites with traditional farming lifestyle. Allergy, 76(11), 3489–3503.

Abstract: Background: Growing up on traditional, single-family farms is associated with protection against asthma in school age, but the mechanisms against early manifestations of atopic disease are largely unknown. We sought determine the gut microbiome and metabolome composition in rural Old Order Mennonite (OOM) infants at low risk and Rochester, NY urban/suburban infants at high risk for atopic diseases. Methods: In a cohort of 65 OOM and 39 Rochester mother-infant pairs, 101 infant stool and 61 human milk samples were assessed by 16S rRNA gene sequencing for microbiome composition and qPCR to quantify Bifidobacterium spp. and B. longum ssp. infantis (B. infantis), a consumer of human milk oligosaccharides (HMOs). Fatty acids (FAs) were analyzed in 34 stool and human 24 milk samples. Diagnoses and symptoms of atopic diseases by 3 years of age were assessed by telephone. Results: At a median age of 2 months, stool was enriched with Bifidobacteriaceae, Clostridiaceae, and Aerococcaceae in the OOM compared with Rochester infants. B. infantis was more abundant (p < .001) and prevalent, detected in 70% of OOM compared with 21% of Rochester infants (p < .001). Stool colonized with B. infantis had higher levels of lactate and several medium- to long/odd-chain FAs. In contrast, paired human milk was enriched with a distinct set of FAs including butyrate. Atopic diseases were reported in 6.5% of OOM and 35% of Rochester children (p < .001). Conclusion: A high rate of B. infantis colonization, similar to that seen in developing countries, is found in the OOM at low risk for atopic diseases. Keywords: Bifidobacterium; allergy; farming lifestyle; human milk; microbiome.

Kim, S., Colaiacovo, S., Dave, S., Coughlin, K., Langdon, K., Stein, R. & Saleh, M. (2021). Aromatase deficiency in an Ontario Old Order Mennonite family. Journal of Pediatric Endocrinology and Metabolism, 34(12), 1615-1618.

Abstract: Background: Aromatase deficiency is a rare autosomal recessive disease that results in the absence of aromatase. In females it presents with ambiguous genitalia and lack of secondary sexual characteristics during puberty. Aromatase deficiency is not attributed to any specific population, but it is more commonly seen in consanguineous parents. Herein, we report the first Old Order Mennonite family with that diagnosis. Case presentation: Our proband is an Old Order Mennonite female born with ambiguous genitalia who was identified to carry novel homozygous variant in the CYP19A1 gene c.1304G>A (p. Arg435His). Her older brother was later confirmed with the same genetic diagnosis. Conclusions: Recognizing the cultural sensitivity, unrecognized affected cases, and late presentation of males affected with aromatase deficiency, this condition may be more prevalent than believed in that population. Keywords: ambiguous genitalia; aromatase deficiency; Old Order Mennonite

Andrew T. Chen, Hannah D. Stacey, Art Marzok, Pardeep Singh, Jann Ang, Matthew S. Miller, Mark Loeb. (2021). Effect of inactivated influenza vaccination on human coronavirus infection: Secondary analysis of a randomized trial in Hutterite colonies. Vaccine, 39(48), 7058-7065.

Abstract: Background: Although influenza vaccines provide protection against influenza viruses, concern has been raised that they may increase susceptibility to non-influenza respiratory viruses. As pandemic lockdowns end, temporal overlap of circulation of seasonal influenza viruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is expected. Understanding the impact of influenza vaccination on risk of coronavirus infection is therefore of considerable public health importance. Methods: We performed a secondary analysis of a randomized trial where children and adolescents in Canadian Hutterite colonies were randomly assigned by colony to receive the 2008–2009 seasonal inactivated trivalent influenza vaccine (TIV) or a control hepatitis A (HepA) vaccine. All 3273 colony members (vaccinated children and nonvaccine recipients) were followed for the primary outcome of RT-PCR confirmed seasonal coronavirus infection. Serum collected pre- and post-vaccination was analyzed for titers of IgG antibodies towards human coronaviruses (HCoV). Results: The incidence of coronavirus infection was 0·18/1000 person-days in the colonies that received TIV vs 0.36/1000 person-days in the control group, hazard ratio (HR) 0.49 [0.21–1.17]. The risk reduction among non-vaccine recipients in the TIV group compared to the control group was HR 0.55 [0.24–1.23]. There was an increase in the geometric mean fold change of HCoV-OC43 antibody titers following TIV compared to HepA vaccine (mean difference 1.2 [0.38–2.06], p = 0.007), and an increase in geometric mean HCoV-NL63 antibody titers post-TIV (262.9 vs 342.9, p = 0.03). Conclusion:The influenza vaccine does not increase the risk of a coronavirus infection. Instead, the influenza vaccine may reduce the rate of coronavirus infections by inducing cross-reactive anti-coronavirus IgG antibodies. Keywords: Influenza, Coronavirus, Vaccine, Clinical epidemiology, Bystander activation

Janine Hutson, Victoria Mok Siu, C. Anthony Rupar. (2022). Clinical Conundrum: Polyhydramnios as a Marker for a Fetal Genetic Syndrome in the Canadian Old Order Mennonite Population. Journal of Obstetrics and Gynaecology Canada, 44 (7), 798-802.

Abstract: A 35-year-old woman was referred to genetics for 2 soft markers but was also found to have polyhydramnios. The couple were Old Order Mennonite, and carrier testing allowed for targeted investigation of syndromes associated with polyhydramnios in this population. Both parents were carriers of a 7304 bp deletion in the STRADA (LYK5) gene, causing an autosomal recessive syndrome of polyhydramnios, megalencephaly, and symptomatic epilepsy. This led to early recognition and treatment of neonatal seizures. Targeted testing can significantly shorten the diagnostic odyssey and decrease the cost of investigations, an especially important consideration for families who do not accept health insurance. Keywords: polyhydramnios; Amish; Mennonite; epilepsy; megalencephaly; prenatal diagnosis

Holmes, C., Aravinthan, K., Murphy, R. A., Gore-Hickman, R., Nair, S. P., & Sharma, A. R. (2022). Idiopathic subglottic stenosis in Saskatchewan Hutterite population. The Journal of laryngology and otology, 136(6), 554–558.

Abstract: Background: By studying the odds of developing idiopathic subglottic stenosis in the isolated and genetically unique Hutterite population, this study sought to strengthen the hypothesis that an underlying genetic predisposition may exist for its development. Methods: A retrospective chart review examined the medical records of all adult patients treated for idiopathic subglottic stenosis in Saskatchewan between 2008 and 2018. Cases were segregated into Hutterite and non-Hutterite. Results: Four out of 36 cases of idiopathic subglottic stenosis occurred among Hutterites. The odds of a Hutterite developing idiopathic subglottic stenosis are 21.89 times higher than for non-Hutterites. Positive family history was only observed in the Hutterite population. Conclusion: The study strengthens the hypothesis that genetics may play a role in the aetiology of idiopathic subglottic stenosis by demonstrating that the genetically and socially unique Hutterites are more likely to develop this rare disease. This study is the first to demonstrate that a specific subpopulation is at a higher risk for developing idiopathic subglottic stenosis. Keywords: Genetic Predisposition To Disease; Incidence; Otolaryngology; Rare Diseases; Subglottic Stenosis.

Humphries, E.M., Ahn, K., Kember, R.L., Lopes, F.L., Mocci, E., Peralta, J.M., Consortium, B.S., Blangero, J., Glahn, D.C., Goes, F.S., Zandi, P.P., Kochunov, P., Van Hout, C.V., Shuldiner, A.R., Pollin, T.I., Mitchell, B.D., Bucan, M., Hong, L.E., McMahon, F.J., & Ament, S.A. (2022). Genome-wide significant risk loci for mood disorders in the Old Order Amish founder population. medRxiv.

Abstract: Background: Genome-wide association studies (GWAS) of mood disorders in large case-control cohorts have identified numerous risk loci, yet pathophysiological mechanisms remain elusive, primarily due to the very small effects of common variants. Methods: We sought to discover risk variants with larger effects by conducting a genome-wide association study of mood disorders in a founder population, the Old Order Amish (OOA, n=1,672). Results: Our analysis revealed four genome-wide significant risk loci, all of which were associated with >2-fold relative risk. Quantitative behavioral and neurocognitive assessments (n=314) revealed effects of risk variants on sub-clinical depressive symptoms and information processing speed. Network analysis suggested that OOA-specific risk loci harbor novel risk-associated genes that interact with known neuropsychiatry-associated genes via gene interaction networks. Annotation of the variants at these risk loci revealed population-enriched, non-synonymous variants in two genes encoding neurodevelopmental transcription factors, CUX1 and CNOT1. Conclusions: Our findings provide insight into the genetic architecture of mood disorders and a substrate for mechanistic and clinical studies. Keywords: GWAS, bipolar disorder, major depression, founder population

Montasser, M.E., Aslibekyan, S., Srinivasasainagendra, V. et al. An Amish founder population reveals rare-population genetic determinants of the human lipidome. (2022). Commun Biol 5, 334.

Abstract: Identifying the genetic determinants of inter-individual variation in lipid species (lipidome) may provide deeper understanding and additional insight into the mechanistic effect of complex lipidomic pathways in CVD risk and progression beyond simple traditional lipids. Previous studies have been largely population based and thus only powered to discover associations with common genetic variants. Founder populations represent a powerful resource to accelerate discovery of previously unknown biology associated with rare population alleles that have risen to higher frequency due to genetic drift. We performed a genome-wide association scan of 355 lipid species in 650 individuals from the Amish founder population including 127 lipid species not previously tested. To the best of our knowledge, we report for the first time the lipid species associated with two rare-population but Amish-enriched lipid variants: APOB_rs5742904 and APOC3_rs76353203. We also identified novel associations for 3 rare-population Amish-enriched loci with several sphingolipids and with proposed potential functional/causal variant in each locus including GLTPD2_rs536055318, CERS5_rs771033566, and AKNA_rs531892793. We replicated 7 previously known common loci including novel associations with two sterols: androstenediol with UGT locus and estriol with SLC22A8/A24 locus. Our results show the double power of founder populations and detailed lipidome to discover novel trait-associated variants. Keywords: biomarkers, lipidome, genetics, CVD risk, founder population

Lynch, M. T., Maloney, K. A., Pollin, T. I., Streeten, E. A., Puffenberger, E. G., Strauss, K. A., Regeneron Genetics Center, Shuldiner, A. R., & Mitchell, B. D. (2022). Impact of parental relatedness on reproductive outcomes among the Old Order Amish of Lancaster County. American journal of medical genetics. Part A, 188(7), 2119–2128. Abstract: Genetically isolated populations that arise due to recent bottleneck events have reduced genetic variation reflecting the common set of founders. Increased genetic relatedness among members of isolated populations puts them at increased risk for some recessive disorders that are rare in outbred populations. To assess the burden on reproductive health, we compared frequencies of adverse reproductive outcomes between Amish couples who were both heterozygous carriers of a highly penetrant pathogenic or likely pathogenic variant and noncarrier couples from the same Amish community. In addition, we evaluated whether overall genetic relatedness of parents was associated with reproductive outcomes. Of the 1824 couples included in our study, 11.1% were at risk of producing a child with an autosomal recessive disorder. Carrier couples reported a lower number of miscarriages compared to noncarrier couples (p = 0.02), although the number of stillbirths (p = 0.3), live births (p = 0.9), and number of pregnancies (p = 0.9) did not differ significantly between groups. In contrast, higher overall relatedness between spouses was positively correlated with number of live births (p < 0.0001), pregnancies (p < 0.0001), and stillbirths (p = 0.03), although not with the number of miscarriages (p = 0.4). These results highlight a complex association between relatedness of parents and reproductive health outcomes in this community. Keywords: founder genetics; parity; reproductive outcomes. Scott, E. M., Wenger, O. K., Robinson, E., Colling, K., Brown, M. F., Hershberger, J., & Radhakrishnan, K. (2022). Glycogen storage disease type 1a in the Ohio Amish. JIMD reports, 63(5), 453–461. Abstract: Glycogen storage disease type 1a (GSD1a) is an inborn error of glucose metabolism characterized by fasting hypoglycemia, hepatomegaly, and growth failure. Late complications include nephropathy and hepatic adenomas. We conducted a retrospective observational study on a cohort of Amish patients with GSD1a. A total of 15 patients cared for at a single center, with a median age of 9.9 years (range 0.25-24 years) were included. All patients shared the same founder variant in GCPC c.1039 C > T. The phenotype of this cohort demonstrated good metabolic control with median cohort triglyceride level slightly above normal, no need for continuous overnight feeds, and a higher quality of life compared to a previous GSD cohort. The most frequent complications were oral aversion, gross motor delay, and renal hyperfiltration. We discuss our unique care delivery at a single center that cares for Amish patients with inherited disorders. Keywords: gross motor delay; hepatomegaly; hypertriglyceridemia; hypoglycemia; oral aversion; quality of life. Michael D. Osterman, Yeunjoo E. Song, Muneeswar Nittala, SriniVas R. Sadda, William K. Scott, Dwight Stambolian, Margaret A. Pericak-Vance, Jonathan L. Haines. (2022). Genomewide Association Study of Retinal Traits in the Amish Reveals Loci Influencing Drusen Development and Link to Age-Related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 63(8):17. Abstract: Purpose: The purpose of this study was to identify genetic risk loci for retinal traits, including drusen, in an Amish study population and compare these risk loci to known risk loci of age-related macular degeneration (AMD). Methods: Participants were recruited from Amish communities in Ohio, Indiana, and Pennsylvania. Each participant underwent a basic health history, ophthalmologic examination, and genotyping. A genomewide association analysis (GWAS) was conducted for the presence and quantity of each of three retinal traits: geographic atrophy, drusen area, and drusen volume. The findings were compared to results from a prior large GWAS of predominantly European-ancestry individuals. Further, a genetic risk score for AMD was used to predict the presence and quantity of the retinal traits. Results: After quality control, 1074 participants were included in analyses. Six single nucleotide polymorphisms (SNPs) met criteria for genomewide significance and 48 were suggestively associated across three retinal traits. The significant SNPs were not highly correlated with known risk SNPs for AMD. A genetic risk score for AMD provided significant predictive value of the retinal traits. Conclusions: We identified potential novel genetic risk loci for AMD in a midwestern Amish study population. Additionally, we determined that there is a clear link between the genetic risk of AMD and drusen. Further study, including longitudinal data collection, may improve our ability to define this connection and improve understanding of the biological risk factors underlying drusen development. Keywords: drusen, age-related macular degeneration (AMD), genetics


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