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Muscular A-type lamin-interacting protein (MLIP) is most abundantly expressed in cardiac and skeletal muscle. In vitro and animal studies have shown its regulatory role in myoblast differentiation and in organization of myonuclear positioning in skeletal muscle, as well as in cardiomyocyte adaptation and cardiomyopathy. We report the association of biallelic truncating variation in the MLIP gene with human disease in five individuals from two unrelated pedigrees.Clinical evaluation and exome sequencing were performed in two unrelated families with elevated creatine kinase level.Family 1. A 6-year-old girl born to consanguineous parents of Arab-Muslim origin presented with myalgia, early fatigue after mild-to-moderate physical exertion, and elevated creatine kinase levels up to 16,000 U/L. Exome sequencing revealed a novel homozygous nonsense variant, c.2530CT; p.Arg844Ter, in the MLIP gene. Family 2. Three individuals from two distantly related families of Old Order Amish ancestry presented with elevated creatine kinase levels, one of whom also presented with abnormal electrocardiography results. On exome sequencing, all showed homozygosity for a novel nonsense MLIP variant c.1825AT; p.Lys609Ter. Another individual from this pedigree, who had sinus arrhythmia and for whom creatine kinase level was not available, was also homozygous for this variant.Our findings suggest that biallelic truncating variants in MLIP result in myopathy characterized by hyperCKemia. Moreover, these cases of MLIP-related disease may indicate that at least in some instances this condition is associated with muscle decompensation and fatigability during low-to-moderate intensity muscle exertion as well as possible cardiac involvement.

STUDY OBJECTIVES: We hypothesized that sleep duration in the Amish would be longer than in non-Amish. METHODS: Sleep duration was obtained by questionnaire administered to Amish individuals (n = 3,418) and from the 2015–2016 National Health and Nutrition Examination Survey (NHANES; n = 1,912). Self-reported sleep duration was calculated as the difference in usual times that the participants went to bed at night and woke up in the morning. RESULTS: In Amish (43.7 ± 16.7 years) and NHANES (50.0 ± 20.6 years), women had a longer sleep duration than men (P < .0001 in both groups) and sleep was significantly longer in those aged 18–29 years and ≥ 70 years, compared to those aged 30–69 years. Seasonal-adjusted sleep duration was shorter in Amish than that in NHANES (7.8 minutes shorter, age- and sex-adjusted P < .0001). However, Amish were less likely to report sleeping fewer than 7 hours per night (15.4% in Amish versus 20.5% in NHANES, P < .0001). Amish went to bed 80.4 minutes earlier than NHANES and arose 87.6 minutes earlier (age-, sex-, and season-adjusted P < .0001 for both). In the Amish, sleep duration was longer in clerks than in farmers (P < .0001) and was significantly correlated among household members (.15 < r < .62, P < .001), although there was no evidence that this trait was heritable (h(2) approximately 0) after adjustment for household. CONCLUSIONS: The lower frequency of short sleepers in the Amish may contribute to the relatively lower risks of cardiometabolic diseases observed in this population. CITATION: Zhang M, Ryan KA, Wickwire E, Postolache TT, Xu H, Daue M, Snitker S, Pollin TI, Shuldiner AR, Mitchell BD. Self-reported sleep duration and pattern in old order amish and non-amish adults. J Clin Sleep Med. 2019;15(9):1321–1328.

Background: Evidence links Toxoplasma gondii (T. gondii), a neurotropic parasite, with schizophrenia, mood disorders and suicidal behavior, all of which are associated and exacerbated by disrupted sleep. Moreover, low-grade immune activation and dopaminergic overstimulation, which are consequences of T. gondii infection, could alter sleep patterns and duration. Methods: Sleep data on 833 Amish participants [mean age (SD) = 44.28 (16.99) years; 59.06% women] were obtained via self-reported questionnaires that assessed sleep problems, duration and timing. T. gondii IgG was measured with ELISA. Data were analyzed using multivariable logistic regressions and linear mixed models, with adjustment for age, sex and family structure. Results: T. gondii seropositives reported less sleep problems (p < 0.005) and less daytime problems due to poor sleep (p < 0.005). Higher T. gondii titers were associated with longer sleep duration (p < 0.05), earlier bedtime (p < 0.005) and earlier mid-sleep time (p < 0.05). Conclusions: It seems unlikely that sleep mediates the previously reported associations between T. gondii and mental illness. Future longitudinal studies with objective measures are necessary to replicate our findings.

Background: In population-based research exome sequencing, the path from variant discovery to return of results is not well established. Variants discovered by research exome sequencing have the potential to improve population health. Methods: Population-based exome sequencing and agnostic ExWAS were performed 5521 Amish individuals. Additional phenotyping and in vitro studies enabled reclassification of a KCNQ1 variant from variant of unknown significance to pathogenic. Results were returned to participants in a community setting. Results: A missense variant was identified in KCNQ1 (c.671C>T, p.T224M), a gene associated with long QT syndrome type 1, which can cause syncope and sudden cardiac death. The p.T224M variant, present in 1/45 Amish individuals is rare in the general population (1/248 566 in gnomAD) and was highly associated with QTc on electro-cardiogram ( P =5.53E-24, β=20.2 ms/allele). Because of the potential importance of this variant to the health of the population, additional phenotyping was performed in 88 p.T224M carriers and 54 noncarriers. There was stronger clinical evidence of long QT syndrome in carriers (38.6% versus 5.5%, P =0.0006), greater history of syncope (32% versus 17%, P =0.020), and higher rate of sudden cardiac death in first degree relativesP =0.026). Expression of p.T224M KCNQ1 in Chinese hamster ovary cells showed near complete loss of protein function. Our clinical and functional data enabled reclassification of p.T224M from a variant of unknown significance to pathogenic. Of the 88 carriers, 93% met criteria for beta-blocker treatment and 5/88 (5.7%) were on medications that may further prolong QTc. Carriers were provided a Clinical Laboratory Improvement Amendments confirmed report, genetic counseling, and treatment recommendations. Follow-up care was coordinated with local physicians. Conclusions: This work provides a framework by which research exome sequencing can be rapidly translated in a culturally appropriate manner to directly benefit research participants and enable population precision health.

Objectives Plasma nitrite is a metabolite of nitric oxide and reflects endogenous nitric oxide synthase (NOS) activity. Although plasma nitrites were previously linked with obesity and metabolic syndrome (MetS), the direction of association remains inconsistent, possibly due to sample heterogeneity. In a relatively homogeneous population, we hypothesized that nitrite levels will be positively associated with overweight/obesity and MetS. Methods Fasting nitrite levels were measured in 116 Old Order Amish (78% women). We performed age-and-sex-adjusted ancovas to compare nitrite levels between three groups (a) overweight/obese(-)MetS(-), (b) overweight/obese(+)MetS(-) and (c) overweight/obese(+)MetS)(+). Multivariate linear regressions were conducted on nitrite associations with continuous metabolic variables, with successive adjustments for demographics, body mass index, C-reactive protein and neopterin. Results Nitrite levels were higher in the obese/overweight(+)MetS(+) group than in the other two groups (p

Seasonal changes in non-human animals and seasonal affective disorder (SAD) in humans are associated with immune activation in winter relative to summer. We intended to measure seasonal variation in neopterin, a marker of cellular immunity, and its interactions with gender and seasonality of mood. We studied 320 Amish from Lancaster, PA, USA (men=128; 40%) with an average age [Standard deviation (SD)] of 56.7 (13.9) years. Blood neopterin level was measured with enzyme-linked immunosorbent assay (ELISA). Seasonality was measured with Seasonal Pattern Assessment Questionnaire (SPAQ). Statistical analysis included analysis of covariance (ANCOVAs) and multivariate linear regression. We also investigated interactions of seasonal differences in neopterin with gender, seasonality scores and estimation of SAD diagnosis. We found a significantly higher neopterin level in winter than in summer (p=0.006). There were no significant gender or seasonality interactions. Our study confirmed the hypothesized higher neopterin level in winter. A cross sectional design was our major limitation. If this finding will be replicated by longitudinal studies in multiple groups, neopterin could be used to monitor immune status across seasons in demographically diverse samples, even if heterogeneous in gender distribution, and degree of seasonality of mood.

Introduction 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. Methods 880 Old Order Amish aged 44.8 (SD: 17.2 years); 360 men (40.91%), 520 women (59.09%) responded to an adapted Pittsburgh-Sleep-Quality-Index questionnaire. IgG serointensity to 7 K-capsular P. gingivalis serotypes were measured with ELISAs. We tested for the association of log-transformed serotype IgG intensity and positivity (successively defined as within the top 5% and 25% for each serotype) with sleep parameters (as binary and continuous variables) using linear and logistic regressions, adjusting for age and sex. Results We confirmed no hypothesized associations between any of the sleep problems on the PSQI and K serotype serointensity and seropositivity. Exploratory analysis returned a negative association of log-transformed K3 IgG with daytime sleepiness (p=0.01); however, this did not resist adjustment for multiple comparisons and was inconsistent with the direction of the hypothesis. Conclusion Strengths of the study include the reduced smoking prevalence in the Amish and the relatively homogenous lifestyle, reducing confounding. The results imply P. gingivalis serotypes are not associated with sleep disturbance. Limitations are self-reporting of sleep, cross-sectional approach and limited generalizability. Results do not support an association between P. gingivalis K serotypes and sleep-problems. Support (if any) MVM-CoRE

Toxoplasma gondii (T. gondii) IgG seropositivity and serointensity have been previously associated with suicidal self-directed violence (SSDV). Although associations with unipolar depression have also been investigated, the results have been inconsistent, possibly as a consequence of high heterogeneity. We have now studied this association in a more homogeneous population, [that is (i.e.) Old Order Amish (OOA)] with previously reported high T. gondii seroprevalence. In 306 OOA with a mean age of 46.1±16.7 years, including 191 (62.4%) women in the Amish Wellness Study, we obtained both T. gondii IgG titers (by enzyme-linked immunosorbent assay [ELISA]), and depression screening questionnaires (Patient Health Questionnaire [PHQ-9] [n=280] and PHQ-2 [n=26]). Associations between T. gondii IgG and dysphoria/hopelessness and anhedonia scores on depression screening questionnaires were analyzed using multivariable linear methods with adjustment for age and sex. Serointensity was associated with both current dysphoria/hopelessness (p=0.045) and current combined anhedonia and dysphoria/hopelessness (p=0.043), while associations with simple anhedonia and past/lifelong (rather than current) phenotypes were not significant. These results indicate the need for larger longitudinal studies to corroborate the association between dysphoria/hopelessness and T. gondii IgG-titers. Current hopelessness is a known risk factor for SSDV which responds particularly well to cognitive behavioral therapy, and may be a focused treatment target for T. gondii-positive individuals at high-risk for SSDV.

Toxoplasma gondii (T. gondii) is an intracellular parasite infecting one third of the world&rsquo, s population. Latent T. gondii infection has been associated with mental illness, including schizophrenia and suicidal behavior. T. gondii IgG antibody titers were measured via ELISA. The heritability of T. gondii IgG was estimated using a mixed model that included fixed effects for age and sex and random kinship effect. Of 2017 Old Order Amish participants, 1098 had positive titers (54.4%). The heritability for T. gondii serointensity was estimated to be 0.22 (p = 1.7 &times, 10&minus, 8 and for seropositivity, it was estimated to be 0.28 (p = 1.9 &times, 5). Shared household environmental effects (i.e., household effects) were also determined. Household effects, modeled as a random variable, were assessed as the phenotypic covariance between any two individuals who had the same current address (i.e., contemporaneous household), and nuclear household (i.e., the phenotypic covariance between parents and children only, not other siblings or spouses). Household effects did not account for a significant proportion of variance in either T. gondii serointensity or T. gondii seropositivity. Our results suggest a significant familial aggregation of T. gondii serointensity and seropositivity with significant heritability. The shared household does not contribute significantly to family aggregation with T. gondii, suggesting that there are possible unmeasured non-household shared and non-shared environmental factors that may play a significant role. Furthermore, the small but significant heritability effects justify the exploration of genetic vulnerability to T. gondii exposure, infection, virulence, and neurotropism.