Family Cohort Research Articles

Abstract MP08: Using Electronic Health Record Data To Link Families: The Pythonic Relationship Inference From The Electronic Health Record Algorithm

Introduction: Intergenerational patterns are an important part of understanding disease, but much of the family-based research can be costly or biased. Emergency contacts in electronic health records (EHR) can be used to link family members using a population that is more representative of a community than traditional family cohort studies. Hypothesis: Creating family trees using emergency contacts will result in robust data that can be used in intergenerational research. Methods: We revised a published algorithm: relationship inference from the electronic health record (RIFTEHR). Our version, pythonic RIFTEHR (P-RIFTEHR) was run on 8/5/21 in the Northwestern Medicine Electronic Data Warehouse (NMEDW) on approximately 3.7 million individuals and was validated using the existing link between children born at NM hospitals and their mothers as the gold-standard. As proof-of-concept, we modeled the association between parent and child obesity using logistic regression. Results: The P-RIFTEHR algorithm matched 1,427,622 individuals in 500,408 families. The median family size is 2, the largest family is approximately 300 persons, and 115 families span four generations or more. Of the EDW-linked mother-child pairs, all matching pairs in P-RIFTEHR were correctly identified as mother-child, resulting in 100% sensitivity. Children are two times more likely to be obese if a parent is obese (OR: 2.01; 95% CI: 1.94, 2.09). This association persists after adjustment (OR: 2.19; 95% CI: 2.10, 2.28) and in mixed models nesting children within parents (OR: 2.70; 95% CI: 2.56, 2.85). Conclusions: P-RIFTEHR works well in a large, diverse population in an integrated health system. Our obesity results are consistent with the literature, including a 2017 meta-analysis by Wang, et al, showing a strong parent-child obesity association (pooled OR: 2.22; 95% CI: 2.09, 2.36). While the information used in the EHR can be completely deidentified, privacy concerns will be addressed before these data are more widely available for research.

Impact of smoking on cardiovascular risk and premature ageing: Findings from the STANISLAS cohort

Background and aimsSmoking may lead to premature ageing, but the impact on the cardiovascular system and circulating proteins needs further investigation. In the present study, we aim to understand the impact of smoking on heart and vessels and circulating biomarkers of multiple domains including cardiovascular damage, premature ageing and cancer-related pathways. MethodsThe STANISLAS Cohort is a longitudinal familial cohort with detailed cardiovascular examination and biomarker assessment. This study included all the participants enrolled in the fourth visit of the STANISLAS Cohort for whom information on smoking habits was available (n = 1696). We assessed pulse wave velocity, intima-media thickness, echocardiographic parameters and a total of 460 proteins to study the association of circulating plasma proteins with smoking status (never vs. past vs. current smoking) while adjusting for potential confounders. ResultsCurrent smokers were approximately 18 years younger but had higher left ventricular mass index (LVMi) and similar pulse wave velocity (PWV), carotid intima media thickness (cIMT), frequency of hypertension, diabetes and carotid plaques compared to the much older never smokers. After multivariate selection, 25 proteins were independently associated with current or past smoking. Current smoking was strongly associated with higher levels of EDIL-3, CCL11, TNFSF13B, KIT, and lower levels of IL-12B and PLTP (p < 0.0001) while past smoking was associated with FGF-21, CHIT1, and lower levels of CXCL10, IL1RL2 and RAGE (p < 0.01). ConclusionsCurrent smoking is associated with signs of early onset of cardiovascular ageing and protein biomarkers that regulate inflammation, endothelial function, metabolism, oncological processes and apoptosis.

Changes in children's wellbeing in Bradford during COVID-19: The Born in Bradford COVID-19 longitudinal research study.

Background: Concerns have been raised about the potential impact of COVID-19 and associated lockdown measures on child mental wellbeing, but emerging evidence suggests mixed results and there is a dearth of information from ethnically diverse samples. The current study aims to explore the impact of the pandemic on wellbeing using longitudinal data collected from the multi-ethnic Born in Bradford family cohort study. Methods: Within-child changes in wellbeing were explored using data collected pre-pandemic and again during the first UK lockdown for 500 children aged 7-13 from a range of ethnic and socioeconomic backgrounds, using self-reported feelings of happiness and sadness. Associations between changes in wellbeing, demographic factors, quality of social relationships and physical activity levels were explored using multinomial logistic regression models. Results: In this sample, 55% of children reported no change in their wellbeing from pre-pandemic to during the first lockdown (n=264). Children of Pakistani heritage were more than twice as likely to report feeling sad less often than White British children (RRR: 2.61, 95% CI: 1.23, 5.51) during the first lockdown, and those who reported being left out by other children before the pandemic were over three times as likely than those who did not (RRR: 3.72: 1.51, 9.20) to report feeling sad less often during the pandemic. Around a third of children reported feeling happier (n=152, 31.6%), but these changes did not relate to any of the explanatory variables included in this analysis. Conclusion: Many children in this study reported no changes in their wellbeing during the first UK lockdown compared to before the pandemic and some described improved wellbeing. These findings suggest that children have coped well with the significant changes over the past year, though targeted support, particularly for those children who felt excluded before the pandemic, would be beneficial.

Progranulin mutations in clinical and neuropathological Alzheimer's disease.

Progranulin (GRN) mutations occur in frontotemporal lobar degeneration (FTLD) and in Alzheimer's disease (AD), often with TDP-43 pathology. We determined the frequency of rs5848 and rare, pathogenic GRN mutations in two autopsy and one family cohort. We compared Braak stage, β-amyloid load, hyperphosphorylated tau (PHFtau) tangle density and TDP-43 pathology in GRN carriers and non-carriers. Pathogenic GRN mutations were more frequent in all cohorts compared to the Genome Aggregation Database (gnomAD), but there was no evidence for association with AD. Pathogenic GRN carriers had significantly higher PHFtau tangle density adjusting for age, sex and APOE ε4 genotype. AD patients with rs5848 had higher frequencies of hippocampal sclerosis and TDP-43 deposits. Twenty-two rare, pathogenic GRN variants were observed in the family cohort. GRN mutations in clinical and neuropathological AD increase the burden of tau-related brain pathology but show no specific association with β-amyloid load or AD.

Does Where You Live Predict What You Say? Associations between Neighborhood Factors, Child Sleep, and Language Development.

Language ability is strongly related to important child developmental outcomes. Family-level socioeconomic status influences child language ability; it is unclear if, and through which mechanisms, neighborhood-level factors impact child language. The current study investigated the association between neighborhood factors (deprivation and disorder) assessed before birth and child language outcomes at age 5, with sleep duration as a potential underlying pathway. Secondary analysis was conducted on data collected between 2008 and 2018 on a subsample of 2444 participants from the All Our Families cohort study (Calgary, Canada) for whom neighborhood information from pregnancy could be geocoded. Neighborhood deprivation was determined using the Vancouver Area Neighborhood Deprivation Index (VANDIX), and disorder was assessed using crime reports. Mothers reported on their children’s sleep duration and language ability. Multilevel modeling indicated that greater neighborhood deprivation and disorder during pregnancy were predictive of lower scores on the Child Communication Checklist–2 (CCC–2) at 5 years. Path analyses revealed an indirect effect of neighborhood disorder on language through child sleep duration at 12 months. These results add to growing evidence that child development should be considered within the context of multiple systems. Sleep duration as an underlying link between environmental factors and child language ability warrants further study as a potential target for intervention.

Linkage analysis identifies novel genetic modifiers of microbiome traits in families with inflammatory bowel disease

ABSTRACT Dysbiosis of the gut microbiome is a hallmark of inflammatory bowel disease (IBD) and both, IBD risk and microbiome composition, have been found to be associated with genetic variation. Using data from families of IBD patients, we examined the association between genetic and microbiome similarity in a specific IBD context, followed by a genome-wide quantitative trait locus (QTL) linkage analysis of various microbiome traits using the same data. SNP genotypes as well as gut microbiome and phenotype data were obtained from the Kiel IBD family cohort (IBD-KC). The IBD-KC is an ongoing prospective study in Germany currently comprising 256 families with 455 IBD patients and 575 first- and second-degree relatives. Initially focusing upon known IBD risk loci, we noted a statistically significant (FDR<0.05) association between genetic similarity at SNP rs11741861 and overall microbiome dissimilarity among pairs of relatives discordant for IBD. In a genome-wide QTL analysis, 12 chromosomal regions were found to be linked to the abundance of one of seven microbial genera, namely Barnesiella (chromosome 4, region spanning 10.34 cM), Clostridium_XIVa (chr4, 3.86 cM; chr14, two regions spanning 7.05 and 13.02 cM respectively), Pseudoflavonifractor (chr7, 12.80 cM) Parasutterella (chr14, 8.26 cM), Ruminococcus (chr16, two overlapping regions spanning 8.01 and 16.87 cM, respectively), Roseburia (chr19, 7.99 cM), and Odoribacter (chr22, three regions spanning 0.89, 5.57 and 1.71 cM, respectively), as well as the Shannon index of α diversity (chr3, 1.47 cM). Our study thus shows that, in families of IBD patients, pairwise genetic similarity for at least one IBD risk locus is associated with overall microbiome dissimilarity among discordant pairs of relatives, and that hitherto unknown genetic modifiers of microbiome traits are located in at least 12 human genomic regions.

Application of Whole Exome Sequencing and Functional Annotations to Identify Genetic Variants Associated with Marfan Syndrome.

Marfan syndrome (MFS) is a rare disease that affects connective tissue, which causes abnormalities in several organ systems including the heart, eyes, bones, and joints. The autosomal dominant disorder was found to be strongly associated with FBN1, TGFBR1, and TGFBR2 mutations. Although multiple genetic mutations have been reported, data from Asian populations are still limited. As a result, we utilized the whole exome sequencing (WES) technique to identify potential pathogenic variants of MFS in a Taiwan cohort. In addition, a variety of annotation databases were applied to identify the biological functions as well as the potential mechanisms of candidate genes. In this study, we confirmed the pathogenicity of FBN1 to MFS. Our results indicated that TTN and POMT1 may be likely related to MFS phenotypes. Furthermore, we found nine unique variants highly shared in a MFS family cohort, of which eight are novel variants worthy of further investigation.

Relative Deprivation, Income Inequality, and Cardiovascular Health: Observational and Mendelian Randomization Studies in Hong Kong Chinese.

The associations between absolute vs. relative income at the household or neighborhood level and cardiovascular disease (CVD) risk remain understudied in the Chinese context. Further, it is unclear whether stress biomarkers, such as cortisol, are on the pathway from income to CVD risk. We examined the associations of absolute and relative income with CVD risk observationally, as well as the mediating role of cortisol, and validated the role of cortisol using Mendelian Randomization (MR) in Hong Kong Chinese. Within Hong Kong's FAMILY Cohort, associations of absolute and relative income at both the individual and neighborhood levels with CVD risk [body mass index (BMI), body fat percentage, systolic blood pressure, diastolic blood pressure, self-reported CVD and self-reported diabetes] were examined using multilevel logistic or linear models (n = 17,607), the mediating role of cortisol using the mediation analysis (n = 1,562), and associations of genetically predicted cortisol with CVD risk using the multiplicative generalized method of moments (MGMMs) or two-stage least squares regression (n = 1,562). In our cross-sectional observational analysis, relative household income deprivation (per 1 SD, equivalent to USD 128 difference in Yitzhaki index) was associated with higher systolic blood pressure (0.47 mmHg, 95% CI 0.30–0.64), but lower BMI (−0.07 kg/m2, 95% CI −0.11 to −0.04), independent of absolute income. Neighborhood income inequality was generally unrelated to CVD and its risk factors, nor was absolute income at the household or neighborhood level. Cortisol did not clearly mediate the association of relative household income deprivation with systolic blood pressure. Using MR, cortisol was unrelated to CVD risk. Based on our findings, relative household income deprivation was not consistently associated with cardiovascular health in Hong Kong Chinese, nor were neighborhood income inequality and absolute income, highlighting the context-specific ways in which relative and absolute income are linked to CVD risk.

Variation and transmission of the human gut microbiota across multiple familial generations

Although the composition and functional potential of the human gut microbiota evolve over the lifespan, kinship has been identified as a key covariate of microbial community diversification. However, to date, sharing of microbiota features within families has mostly been assessed between parents and their direct offspring. Here we investigate the potential transmission and persistence of familial microbiome patterns and microbial genotypes in a family cohort (n = 102) spanning 3 to 5 generations over the same female bloodline. We observe microbiome community composition associated with kinship, with seven low abundant genera displaying familial distribution patterns. While kinship and current cohabitation emerge as closely entangled variables, our explorative analyses of microbial genotype distribution and transmission estimates point at the latter as a key covariate of strain dissemination. Highest potential transmission rates are estimated between sisters and mother–daughter pairs, decreasing with increasing daughter’s age and being higher among cohabiting pairs than those living apart. Although rare, we detect potential transmission events spanning three and four generations, primarily involving species of the genera Alistipes and Bacteroides. Overall, while our analyses confirm the existence of family-bound microbiome community profiles, transmission or co-acquisition of bacterial strains appears to be strongly linked to cohabitation.

Predictors of Preadolescent Children's Recreational Screen Time Duration During the COVID-19 Pandemic.

Research suggests that children's screen use during the COVID-19 pandemic has doubled. There is a need to understand factors associated with increased use to more adequately inform COVID-19 pandemic recovery efforts aimed at promoting healthy device habits. The objective of this multi-informant study of children aged 9 to 11 years was to examine whether duration of screen use during the COVID-19 pandemic was predicted by sociodemographic factors (e.g., child age and sex), COVID-19 pandemic family stressors, daily routines (e.g., sleep and physical activity), and device use factors (e.g., parent management strategies and content and context of use). Participants included 846 children (M = 9.85, SD = 0.78) and their mothers from the All Our Families cohort, Calgary, Canada. Mothers reported (May-July 2020) on child screen use and COVID-19 pandemic impacts (e.g., job/income loss and stress), and children self-reported (July-August 2020) on their screen use and daily routines (e.g., sleep, physical activity, and device-free activities). Screen use during the COVID-19 pandemic was highest among male and minoritized children and families reporting high levels of stress. Children had lower durations of screen time when device limits were set by mothers. Children also had lower durations of screen time when they used screens to connect with others and when they engaged in higher levels of physical activity or device-free recreational activities. This study sheds light on children's screen use during the COVID-19 pandemic and supports the current screen use guidelines for school-aged children, suggesting that parents monitor use and foster high-quality screen use (e.g., coviewing or used for connection) and device-free recreational activities when possible.

Soluble AXL is a novel blood marker for early detection of pancreatic ductal adenocarcinoma and differential diagnosis from chronic pancreatitis.

SummaryBackgroundEarly diagnosis is crucial for patients with pancreatic ductal adenocarcinoma (PDAC). The AXL receptor tyrosine kinase is proteolytically processed releasing a soluble form (sAXL) into the blood stream. Here we explore the use of sAXL as a biomarker for PDAC.MethodsAXL was analysed by immunohistochemistry in human pancreatic tissue samples. RNA expression analysis was performed using TCGA/GTEx databases. The plasma concentrations of sAXL, its ligand GAS6, and CA19-9 were studied in two independent cohorts, the HMar cohort (n = 59) and the HClinic cohort (n = 142), including healthy controls, chronic pancreatitis (CP) or PDAC patients, and in a familial PDAC cohort (n = 68). AXL expression and sAXL release were studied in PDAC cell lines and murine models.FindingsAXL is increased in PDAC and precursor lesions as compared to CP or controls. sAXL determined in plasma from two independent cohorts was significantly increased in the PDAC group as compared to healthy controls or CP patients. Patients with high levels of AXL have a lower overall survival. ROC analysis of the plasma levels of sAXL, GAS6, or CA19-9 in our cohorts revealed that sAXL outperformed CA19-9 for discriminating between CP and PDAC. Using both sAXL and CA19-9 increased the diagnostic value. These results were validated in murine models, showing increased sAXL specifically in animals developing PDAC but not those with precursor lesions or acinar tumours.InterpretationsAXL appears as a biomarker for early detection of PDAC and PDAC–CP discrimination that could accelerate treatment and improve its dismal prognosis.FundingThis work was supported by grants PI20/00625 (PN), RTI2018-095672-B-I00 (AM and PGF), PI20/01696 (MG) and PI18/01034 (AC) from MICINN-FEDER and grant 2017/SGR/225 (PN) from Generalitat de Catalunya.

Familial risk and heritability of intellectual disability: a population-based cohort study in Sweden.

Intellectual disability (ID) aggregates in families, but factors affecting individual risk and heritability estimates remain unknown. A population-based family cohort study of 4,165,785 individuals born 1973-2013 in Sweden, including 37,787 ID individuals and their relatives. The relative risks (RR) of ID with 95% confidence intervals (95% CI) were obtained from stratified Cox proportional-hazards models. Relatives of ID individuals were compared to relatives of unaffected individuals. Structural equationmodeling was used to estimate heritability. Relatives of ID individuals were at increased risk of ID compared to individuals with unaffected relatives. The RR of ID among relatives increased proportionally to the degree of genetic relatedness with ID probands; 256.70(95% CI 161.30-408.53) for monozygotic twins, 16.47(13.32-20.38) for parents, 14.88(12.19-18.16) for children, 7.04(4.67-10.61) for dizygotic twins, 8.38(7.97-8.83) for full siblings, 4.56(4.02-5.16) for maternal, 2.90(2.49-3.37) for paternal half-siblings, 3.03(2.61-3.50) for nephews/nieces, 2.84(2.45-3.29) for uncles/aunts, and 2.04(1.91-2.20) for cousins. Lower RRs were observed for siblings of probands with chromosomal abnormalities (RR 5.53, 4.74-6.46) and more severe ID (mild RR 9.15, 8.55-9.78, moderate RR 8.13, 7.28-9.08, severe RR 6.80, 5.74-8.07, and profound RR 5.88, 4.52-7.65). Male sex of relative and maternal line of relationship with proband was related to higher risk (RR 1.33, 1.25-1.41 for brothers vs. sisters and RR 1.49, 1.34-1.68 for maternal vs. paternal half-siblings). ID was substantially heritable with 0.95(95% CI 0.93-0.98) of the variance in liability attributed to genetic influences. The risk estimates will benefit researchers, clinicians, families in understanding the risk of ID in the family and the whole population. The higher risk of ID related to male sex and maternal linage will be of value for planning and interpreting etiological studies in ID.

Skeletal Muscle Quality Of Nonagenarians And Centenarians

Skeletal muscle adipose tissue infiltration is hypothesized to lead to poorer muscle quality and function with aging. Indeed, skeletal muscle adiposity has emerged as a consistent, independent predictor of skeletal muscle strength, mobility, metabolic disorders, and survival among older adults. However, phenotypic features of skeletal muscle among the oldest-old remain poorly characterized. Herein, we evaluated the skeletal muscle characteristics of 54 nonagenarians and centenarians (mean age 98 years, range 90-110 years; 63% women) and 25 middle-aged individuals (mean age 54 years, range 40-59 years; 36% women) belonging to the Long Life Family Study (LLFS), an international, multicenter cohort of families with a clustering of longevity. Ultrasonography was used to measure echo intensity of the sternocleidomastoid muscle, which has a similar fiber type distribution to the rectus femoris. Greater echo intensity is indicative of lower muscle quality (greater adipose and fibrotic tissue). Current smoking, alcohol intake, and BMI were similar between the age groups. Nonagenarians and centenarians had lower grip strength (16.3 vs. 39 kg) and were less physically active (22.2% vs 66.7% exercised 1+ times per week) compared to younger individuals (P<0.001 for all). Mean±SE echo intensity, adjusted for gender, field center, BMI and physical activity was 52.1±1.7 among nonagenarians and centenarians compared to 44.2±2.4 among younger individuals (P=0.0098). Our preliminary findings suggest that nonagenarians and centenarians may have substantially lower skeletal muscle quality and strength compared to their younger aged counterparts. Additional research is needed to better understand the mechanisms leading to poorer muscle characteristics of the oldest-old.

Another Perspective on Huntington's Disease: Disease Burden in Family Members and Pre-Manifest HD When Compared to Genotype-Negative Participants from ENROLL-HD.

Background: In addition to the effects on patients suffering from motor-manifest Huntington’s disease (HD), this fatal disease is devasting to people who are at risk, premanifest mutation-carriers, and especially to whole families. There is a huge burden on people in the environment of affected HD patients, and a need for further research to identify at-risk caregivers. The aim of our research was to investigate a large cohort of family members, in comparison with genotype negative and premanifest HD in order to evaluate particular cohorts more closely. Methods: We used the ENROLL-HD global registry study to compare motoric, cognitive, functional, and psychiatric manifestation in family members, premanifest HD, and genotype negative participant as controls. Cross-sectional data were analyzed using ANCOVA-analyses in IBM SPSS Statistics V.28. Results: Of N = 21,116 participants from the global registry study, n = 5174 participants had a premanifest motor-phenotype, n = 2358 were identified as family controls, and n = 2640 with a negative HD genotype. Analysis of variance revealed more motoric, cognitive, and psychiatric impairments in premanifest HD (all p < 0.001). Self-reported psychiatric assessments revealed a significantly higher score for depression in family controls (p < 0.001) when compared to genotype negative (p < 0.001) and premanifest HD patients (p < 0.05). Family controls had significantly less cognitive capacities within the cognitive test battery when compared to genotype negative participants. Conclusions: Within the largest cohort of HD patients and families, several impairments of motoric, functional, cognitive, and psychiatric components can be confirmed in a large cohort of premanifest HD, potentially due to prodromal HD pathology. HD family controls suffered from higher self-reported depression and less cognitive capacities, which were potentially due to loaded or stressful situations. This research aims to sensitize investigators to be aware of caregiver burdens caused by HD and encourage support with socio-medical care and targeted psychological interventions. In particular, further surveys and variables are necessary in order to implement them within the database so as to identify at-risk caregivers.

Shared familial risk factors between autism spectrum disorder and obesity - a register-based familial coaggregation cohort study.

Meta-analyses suggest an association between autism spectrum disorder (ASD) and obesity, but the factors underlying this association remain unclear. This study investigated the association between ASD and obesity stratified on intellectual disability (ID). In addition, in order to gain insight into possible shared etiological factors, the potential role of shared familial liability was examined. We studied a cohort of 3,141,696 individuals by linking several Swedish nationwide registers. We identified 35,461 individuals with ASD and 61,784 individuals with obesity. Logistic regression models were used to estimate the association between ASD and obesity separately by ID and sex and by adjusting for parental education, psychiatric comorbidity, and psychotropic medication. Potential shared familial etiologic factors were examined by comparing the risk of obesity in full siblings, maternal and paternal half-siblings, and full- and half-cousins of individuals with ASD to the risk of obesity in relatives of individuals without ASD. Individuals with ASD + ID (OR = 3.76 [95% CI, 3.38-4.19]) and ASD-ID (OR = 3.40 [95% CI, 3.23-3.58]) had an increased risk for obesity compared with individuals without ASD. The associations remained statistically significant when adjusting for parental education, psychiatric comorbidity, and medication. Sex-stratified analyses indicated a higher relative risk for males compared with females, with statistically significant interaction effects for ASD-ID, but not for ASD+ID in the fully adjusted model. First-degree relatives of individuals with ASD+ID and ASD-ID had an increased risk of obesity compared with first-degree relatives of individuals without ASD. The obesity risk was similar in second-degree relatives of individuals with ASD+ID but was lower for and ASD-ID. Full cousins of individuals with ASD+ID had a higher risk compared with half-cousins of individuals with ASD+ID). A similar difference in the obesity risk between full cousins and half-cousins was observed for ASD-ID. Individuals with ASD and their relatives are at increased risk for obesity. The risk might be somewhat higher for males than females. This warrants further studies examining potential common pleiotropic genetic factors and shared family-wide environmental factors for ASD and obesity. Such research might aid in identifying specific risks and underlying mechanisms in common between ASD and obesity.

A resilient type of familial hypercholesterolaemia: case–control follow-up of genetically characterized older patients in the SAFEHEART cohort

Knowledge of the features of patients with familial hypercholesterolaemia (FH) who are protected from atherosclerotic cardiovascular disease (ASCVD) is important for the clinical and prognostic care of this apparently high-risk condition. Our aim was to investigate the determinant and characteristics of patients with FH who are protected from ASCVD and have normal life expectancy, so-called 'resilient' FH (R-FH). Spanish Familial Hypercholesterolaemia cohort study (SAFEHEART) is an open, multicentre, nation-wide, long-term prospective cohort study in genetically defined patients with heterozygous FH in Spain. Patients in the registry who at the time of analysis were at least 65 years or those who would have reached that age had they not died from an ASCVD event were analysed as a case-control study. Resilient FH was defined as the presence of a pathogenic mutation causative of FH in a patient aged ≥65 years without clinical ASCVD. Nine hundred and thirty registrants with FH met the study criteria. A defective low-density lipoprotein (LDL)-receptor mutation, higher plasma level of high-density lipoprotein cholesterol (HDL-C), younger age, female gender, absence of hypertension, and lower plasma lipoprotein (a) [Lp(a)] concentration were independently predictive of R-FH. In a second model, higher levels of HDL-C and lower 10-year score in SAFEHEART-RE were also independently predictive of R-FH. Resilient FH may be typified as being female and having a defective LDL-receptor mutation, higher levels of plasma HDL-C, lower levels of Lp(a), and an absence of hypertension. The implications of this type of FH for clinical practice guidelines and the value for service design and optional care of FH remains to be established. ClinicalTrials.gov number NCT02693548.

Genetic Risk in Families with Age-Related Macular Degeneration.

PurposeTo determine the contribution of common and rare genetic risk variants in families with age-related macular degeneration (AMD).DesignCase-control study.ParticipantsA family cohort (355 affected and 342 unaffected family members from 144 families with AMD) and an unrelated case-control cohort (1078 patients, 952 controls), recruited from the European Genetic Database.MethodsGenetic data of both cohorts were filtered for carriership of rare genetic variants in the coding and splice-site regions of the complement factor H (CFH) and complement factor I (CFI) genes, and 52 AMD-associated variants were extracted for calculation of genetic risk scores (GRS). To compare GRSs between familial and nonfamilial rare CFH and CFI variant carriers and noncarriers and between AMD disease stages, we performed a 2-way analysis of variance, with Bonferroni correction for multiple testing. Within families with AMD carrying rare CFH and CFI variants, we analyzed segregation patterns by calculating the proportion of affected among carriers.Main Outcome MeasuresGRSs and segregation of rare CFH and CFI variants.ResultsWe observed higher GRSs in familial versus nonfamilial individuals without rare CFH and CFI variants: mean GRS, 1.76 (standard error [SE], 0.08) versus 0.83 (SE, 0.03; P < 0.001). In 51 of 144 families (35.4%), rare CFH and CFI variants were identified. Within the AMD family cohort, carriers of rare CFH and CFI variants showed lower GRSs compared with noncarriers (mean GRS, 1.05 [SE, 0.23] vs. 1.76 [SE, 0.08]; P = 0.02). The proportion of affected family members with a high GRS was 57.3% (176/307). Of the affected family members with a low or intermediate GRS, 40.0% carried rare CFH or CFI variants. Among carriers of 11 rare CFH or CFI variants, the proportion affected by AMD was more than 75%.ConclusionsGenetic risk in families with AMD often is attributed to high GRSs based on common variants. However, in part of the families with a low or intermediate GRS, rare CFH and CFI variants contributed to disease development. We recommend computing GRSs and sequencing the CFH and CFI genes in families with AMD, in particular in the light of ongoing gene-specific clinical trials.

Socio-demographic and familial factors associated with hospital admissions and repeat admission for dental caries in early childhood: A population-based study.

Dental caries remains a complex childhood condition often requiring preventable hospital admissions. There are limited population-based epidemiological studies that use large and linked data sets to quantify the clinical, socio-demographic and familial risk factors related to hospital admissions for dental caries. The aim of this study was to describe and quantify the rates, socio-demographic, clinical characteristics and familial factors including repeat admissions associated with young children admitted to hospital for dental caries. This cohort study (n=33,438) used longitudinally linked hospital admission data among all children aged <six years in NSW, Australia. Socio-demographic and admission characteristics of children and those with one versus two or more admissions for dental caries were compared. Familial risk factors were analysed for a restricted cohort of families with two or more children (n=18,174) using multivariable logistic regression to assess the familial factors associated with multiple hospital admissions for dental caries adjusting for other socio-demographic characteristics. There were 33,438children aged <six years who had 34,446hospital admissions for dental caries between 2001 and 2014. The annual rate of 4.3 per 1000children remained unchanged over the period. Most admissions required general anaesthesia (96%), and 8.4% of children had repeat admissions. Children living in disadvantaged or in regional and rural areas attending public hospitals were more likely to have dental extractions during the admission. Children from the same family had a 2.7-fold increased odds of admission if the first child admitted was less than three years of age (adjusted odd ratio 2.69; 95% CI: 2.36-3.07), a 1.5 fold increase for socioeconomic disadvantage (aOR 1.45; 1.19 - 1.77) and a 1.9 fold increase of admission if the family had 4 or more children (aOR1.88; 1.47 - 2.42). Findings highlight socio-demographic inequities associated with hospital admission for dental caries. The provision of targeted dental care programs for 'at-risk' families should address these inequalities and presents an opportunity to reduce dental caries related hospitalizations.

Genomic analysis of childhood hearing loss in the Yoruba population of Nigeria

Although variant alleles of hundreds of genes are associated with sensorineural deafness in children, the genes and alleles involved remain largely unknown in the Sub-Saharan regions of Africa. We ascertained 56 small families mainly of Yoruba ethno-lingual ancestry in or near Ibadan, Nigeria, that had at least one individual with nonsyndromic, severe-to-profound, prelingual-onset, bilateral hearing loss not attributed to nongenetic factors. We performed a combination of exome and Sanger sequencing analyses to evaluate both nuclear and mitochondrial genomes. No biallelic pathogenic variants were identified in GJB2, a common cause of deafness in many populations. Potential causative variants were identified in genes associated with nonsyndromic hearing loss (CIB2, COL11A1, ILDR1, MYO15A, TMPRSS3, and WFS1), nonsyndromic hearing loss or Usher syndrome (CDH23, MYO7A, PCDH15, and USH2A), and other syndromic forms of hearing loss (CHD7, OPA1, and SPTLC1). Several rare mitochondrial variants, including m.1555A>G, were detected in the gene MT-RNR1 but not in control Yoruba samples. Overall, 20 (33%) of 60 independent cases of hearing loss in this cohort of families were associated with likely causal variants in genes reported to underlie deafness in other populations. None of these likely causal variants were present in more than one family, most were detected as compound heterozygotes, and 77% had not been previously associated with hearing loss. These results indicate an unusually high level of genetic heterogeneity of hearing loss in Ibadan, Nigeria and point to challenges for molecular genetic screening, counseling, and early intervention in this population.

Estimation of macro- and micro-genetic environmental sensitivity in unbalanced datasets

Genotype-by-environment interaction is caused by variation in genetic environmental sensitivity (GES), which can be subdivided into macro- and micro-GES. Macro-GES is genetic sensitivity to macro-environments (definable environments often shared by groups of animals), while micro-GES is genetic sensitivity to micro-environments (individual environments). A combined reaction norm and double hierarchical generalised linear model (RN-DHGLM) allows for simultaneous estimation of base genetic, macro- and micro-GES effects. The accuracy of variance components estimated using a RN-DHGLM has been explicitly studied for balanced data and recommendation of a data size with a minimum of 100 sires with at least 100 offspring each have been made. In the current study, the data size (numbers of sires and progeny) and structure requirements of the RN-DHGLM were investigated for two types of unbalanced datasets. Both datasets had a variable number of offspring per sire, but one dataset also had a variable number of offspring within macro-environments. The accuracy and bias of the estimated macro- and micro-GES effects and the estimated breeding values (EBVs) obtained using the RN-DHGLM depended on the data size. Reasonably accurate and unbiased estimates were obtained with data containing 500 sires with 20 offspring or 100 sires with 50 offspring, regardless of the data structure. Variable progeny group sizes, alone or in combination with an unequal number of offspring within macro-environments, had little impact on the dispersion of the EBVs or the bias and accuracy of variance component estimation, but resulted in lower accuracies of the EBVs. Compared to genetic correlations of zero, a genetic correlation of 0.5 between base genetic, macro- and micro-GES components resulted in a slight decrease in the percentage of replicates that converged out of 100 replicates, but had no effect on the dispersion and accuracy of variance component estimation or the dispersion of the EBVs. The results show that it is possible to apply the RN-DHGLM to unbalanced datasets to obtain estimates of variance due to macro- and micro-GES. Furthermore, the levels of accuracy and bias of variance estimates when analysing macro- and micro-GES simultaneously are determined by average family size, with limited impact from variability in family size and/or cohort size. This creates opportunities for the use of field data from populations with unbalanced data structures when estimating macro- and micro-GES.