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INTRODUCTION: Growing up in disadvantaged neighborhoods is associated with poor adult health indicators. Consistent and supportive parenting plays a key role in life-long health, but it is not known whether positive parenting can mitigate the relationship between neighborhood adversity and poor health. This study examines parenting as a moderator of the links between childhood neighborhood characteristics and adult health indicators. METHODS: A sample of 305 individuals (61% female; 82% African American, 18% Caucasian) were assessed in childhood (T1; age 11; 2003–2004) and adulthood (T2; age 27; 2018–2021). At T1, neighborhood poverty was derived from census data; neighborhood disorder was reported by parents. Children reported on parental harsh discipline, inconsistent discipline, and parental nurturance. At T2, health outcomes included BMI, serum cortisol and C-reactive protein (CRP), and salivary DNA methylation index related to CRP. Regression models predicted T2 health outcomes from T1 neighborhood and parenting variables and their interactions, adjusting for clustering and confounders. Data were analyzed in 2021. RESULTS: Neighborhood poverty was associated with lower cortisol, whereas neighborhood disorder was linked with CRP-related DNA methylation. Multiple interactions between neighborhood and parenting variables emerged, indicating that adverse neighborhood conditions were only related to poor adult health when combined with inconsistent discipline and low parental nurturance. By contrast, warm and supportive parenting, consistent discipline, and to a lesser extent harsh discipline buffered children from poor health outcomes associated with neighborhood disadvantage. CONCLUSIONS: Interventions enhancing consistent and nurturing parenting may help reduce the long-term associations of neighborhood disadvantage with poor health.

BACKGROUND: Epigenome-wide association studies identified the cg00574958 DNA methylation site at the carnitine palmitoyltransferase-1A (CPT1A) gene to be associated with reduced risk of metabolic diseases (hypertriglyceridemia, obesity, type 2 diabetes, hypertension, metabolic syndrome), but the mechanism underlying these associations is unknown. OBJECTIVES: We aimed to elucidate whether carbohydrate and fat intakes modulate cg00574958 methylation and the risk of metabolic diseases. METHODS: We examined associations between carbohydrate (CHO) and fat (FAT) intake, as percentages of total diet energy, and the CHO/FAT ratio with CPT1A-cg00574958, and the risk of metabolic diseases in 3 populations (Genetics of Lipid Lowering Drugs and Diet Network, n = 978; Framingham Heart Study, n = 2331; and REgistre GIroní del COR study, n = 645) while adjusting for confounding factors. To understand possible causal effects of dietary intake on the risk of metabolic diseases, we performed meta-analysis, CPT1A transcription analysis, and mediation analysis with CHO and FAT intakes as exposures and cg00574958 methylation as the mediator. RESULTS: We confirmed strong associations of cg00574958 methylation with metabolic phenotypes (BMI, triglyceride, glucose) and diseases in all 3 populations. Our results showed that CHO intake and CHO/FAT ratio were positively associated with cg00574958 methylation, whereas FAT intake was negatively correlated with cg00574958 methylation. Meta-analysis further confirmed this strong correlation, with β = 58.4 ± 7.27, P = 8.98 x 10(-16) for CHO intake; β = −36.4 ± 5.95, P = 9.96 x 10(-10) for FAT intake; and β = 3.30 ± 0.49, P = 1.48 x 10(-11) for the CHO/FAT ratio. Furthermore, CPT1A mRNA expression was negatively associated with CHO intake, and positively associated with FAT intake, and metabolic phenotypes. Mediation analysis supports the hypothesis that CHO intake induces CPT1A methylation, hence reducing the risk of metabolic diseases, whereas FAT intake inhibits CPT1A methylation, thereby increasing the risk of metabolic diseases. CONCLUSIONS: Our results suggest that the proportion of total energy supplied by CHO and FAT can have a causal effect on the risk of metabolic diseases via the epigenetic status of CPT1A. Study registration at https://www.clinicaltrials.gov/: the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN)—NCT01023750; and the Framingham Heart Study (FHS)—NCT00005121.

There are limited data from Africa on the burden and associations between pre-diabetes (pre-DM), diabetes mellitus (DM) and stroke occurrence in a region experiencing a profound rise in stroke burden.To characterize the associations between stroke and dysglycemic status among West Africans.The Stroke Investigative Research and Educational Network (SIREN) is a multicenter, case-control study involving 15 sites in Ghana and Nigeria. Cases include adults aged ≥18 years with clinical and radiological evidence of an acute stroke. Controls were age-and-gender matched stroke-free adults. Detailed evaluations for vascular factors were performed. Pre-diabetes was defined as HBA1c of 5.7%-6.4% or Fasting blood glucose (FBG) 5.6-7.0 mmol/L and DM as HBA1c6.5% or FBG7.0 mmol/L. We used conditional logistic regression to estimate adjusted odds ratios (aOR) with 95% Confidence Interval.Among 2,935 stroke cases the mean age was 60.0 ± 14.2 years with 55.2% being males. By glycemic status, 931 (31.7%) were euglycemic, 633 (21.6%) had Pre-diabetes and 1371 (46.7%) had DM. Of the age- and sex-matched stroke-free controls 69.2% were euglycemic, 13.3% had pre-DM and 17.5% had DM. Pre-DM [aOR (95% CI): 3.68(2.61-5.21)] and DM [4.29 (3.19-5.74)] were independently associated with stroke. The aOR of Pre-DM for ischemic stroke 3.06 (2.01-4.64)] was lower than 4.82 (3.37-6.89) for DM. However, the aOR of Pre-DM for hemorrhagic stroke 6.81 (95% CI: 3.29 - 14.08)] was higher than 3.36 (1.94-5.86) for DM. Furthermore, the aOR of pre-DM for ischemic stroke subtypes were 9.64 (1.30-71.57) for cardio-embolic stroke, 3.64 (1.80-7.34) for small-vessel occlusive disease and 4.63 (0.80-26.65) for large-vessel disease.Pre-DM is strongly and independently associated with stroke in Africans. Improving glycemic control through screening, healthy lifestyle and pharmacotherapy at a population level may be strategic in reducing the rising burden of stroke in Africa.

The prognostic implications of metabolic syndrome (METS) among African stroke patients are poorly understood. This study aimed to investigate the determinants of METS and its prognostic implications among Africans with newly diagnosed stroke in the SIREN study.We included stroke cases (adults aged18 years with CT/MRI confirmed stroke). The validated tools comprehensively evaluated vascular, lifestyle, and psychosocial factors. We used logistic regression to estimate adjusted odds ratios (OR) with 95% CIs for the association between METS and risk factors. We also computed the prediction power of the domain of covariates in a sequential manner using the area under the receiver operating curve (ROC) curve.Among 3998 stroke subjects enrolled in the study, 76.8% had METS by at least one of the clinical definitions. Factors associated with METS were age 50 years (OR- 1.46, CI-1.19-1.80), male gender (OR 4.06, CI- 3.28-5.03), income100USD (OR1.42, CI-1.17-1.71), stress (OR1.46, CI-1.14-1.87), family history of diabetes mellitus (OR1.38, CI-1.06-1.78), and cardiac disease (OR1.42, CI-1.18-1.65). Stroke severity was higher among those with METS (SLS = 5.8 ± 4.3) compared with those without METS (6.2 ± 4.5) at p = 0.037. METS was associated with higher odds (aOR 1.31, CI-1.08-1.58) of one-month fatality after adjusting for stroke severity, age 50 years, and average monthly income100USD.METS is very common among African stroke patients and is associated with stroke severity and worse one-month fatality. Lifestyle interventions may prevent METS and attenuate its impact on stroke occurrence and outcomes.

Somatic human cells contain thousands of copies of mitochondrial DNA (mtDNA). In eukaryotes, natural transfer of mtDNA into the nucleus generates nuclear mitochondrial DNA (NUMT) copies. We name this phenomenon as "numtogenesis". Numtogenesis is a well-established evolutionary process reported in various sequenced eukaryotic genomes. We have established a molecular tool to rapidly detect and analyze NUMT insertions in whole genomes. To date, NUMT analyses depend on deep genome sequencing combined with comprehensive computational analyses of the whole genome. This is time consuming, cumbersome and cost prohibitive. Further, most laboratories cannot accomplish such analyses due to limited skills. We report the development of single-molecule mtFIBER FISH (fluorescence in situ hybridization) to study numtogenesis. The development of mtFIBER FISH should aid in establishing a role for numtogenesis in cancers and other human diseases. This novel technique should help distinguish and monitor cancer stages and progression, aid in elucidation of basic mechanisms underlying tumorigenesis and facilitate analyses of processes related to early detection of cancer, screening and/or cancer risk assessment.

Background Stroke risk can be quantified using risk factors whose effect sizes vary by geography and race. No stroke risk assessment tool exists to estimate aggregate stroke risk for indigenous African. Objectives To develop Afrocentric risk-scoring models for stroke occurrence. Materials and Methods We evaluated 3533 radiologically confirmed West African stroke cases paired 1:1 with age-, and sex-matched stroke-free controls in the SIREN study. The 7,066 subjects were randomly split into a training and testing set at the ratio of 85:15. Conditional logistic regression models were constructed by including 17 putative factors linked to stroke occurrence using the training set. Significant risk factors were assigned constant and standardized statistical weights based on regression coefficients (β) to develop an additive risk scoring system on a scale of 0–100%. Using the testing set, Receiver Operating Characteristics (ROC) curves were constructed to obtain a total score to serve as cut-off to discriminate between cases and controls. We calculated sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) at this cut-off. Results For stroke occurrence, we identified 15 traditional vascular factors. Cohen's kappa for validity was maximal at a total risk score of 56% using both statistical weighting approaches to risk quantification and in both datasets. The risk score had a predictive accuracy of 76% (95%CI: 74–79%), sensitivity of 80.3%, specificity of 63.0%, PPV of 68.5% and NPV of 76.2% in the test dataset. For ischemic strokes, 12 risk factors had predictive accuracy of 78% (95%CI: 74–81%). For hemorrhagic strokes, 7 factors had a predictive accuracy of 79% (95%CI: 73–84%). Conclusions The SIREN models quantify aggregate stroke risk in indigenous West Africans with good accuracy. Prospective studies are needed to validate this instrument for stroke prevention.

BACKGROUND: The burden of stroke in Africa is high. Understanding how age associates with major modifiable stroke risk factors could inform tailored demographic stroke prevention strategies. PURPOSE: To quantify the magnitude and direction of the effect sizes of key modifiable stroke risk factors according to three age groups: 65 years (elderly) in West Africa. METHODS: This was a case-control study involving 15 sites in Ghana and Nigeria. Cases included adults aged ≥18 years with CT/MRI scan-typed stroke. Controls were age-and gender-matched stroke-free adults. Detailed evaluations for vascular, lifestyle and psychosocial factors were performed. We estimated adjusted odds ratios (aOR) using conditional logistic regression and population attributable risk (PAR) with 95% Confidence Interval of vascular risk factors by age groups. RESULTS: Among 3553 stroke cases, 813 (22.9%) were young, 1441 (40.6%) were middle-aged and 1299 (36.6%) were elderly. Among the 5 co-shared risk factors, dyslipidemia with PAR and aOR (95%CI) of 62.20% (52.82–71.58) and 4.13 (2.64–6.46) was highest among the young age group; hypertension with PAR of 94.31% (91.82–96.80) and aOR of 28.93 (15.10–55.44) was highest among the middle-age group. Diabetes with PAR of 32.29% (27.52–37.05) and aOR of 3.49 (2.56–4.75); meat consumption with PAR of 42.34%(32.33–52.35) and aOR of 2.40 (1.76, 3.26); and non-consumption of green vegetables, PAR of 16.81%(12.02–21.60) and aOR of 2.23 (1.60–3.12) were highest among the elderly age group. However confidence intervals of risk estimates over-lapped across age groups. Additionally, among the young age group cigarette smoking, psychosocial stress and cardiac disease were independently associated with stroke. Furthermore, education, stress, physical inactivity and salt intake were associated with stroke in the middle-age group while cardiac disease was associated with stroke in the elderly age group. CONCLUSION: There is a differential influence of age on the associations of major risk factors with stroke in this West African cohort. Targeting modifiable factors predominant within an age group may be more effective as a stroke prevention strategy.

BACKGROUND: Trimethylamine-N-oxide (TMAO), an atherogenic metabolite species, has emerged as a possible new risk factor for cardiovascular disease. Animal studies have shown that circulating TMAO levels are regulated by genetic and environmental factors. However, large-scale human studies have failed to replicate the observed genetic associations, and epigenetic factors such as DNA methylation have never been examined in relation to TMAO levels. METHODS AND RESULTS: We used data from the family-based Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) to investigate the heritable determinants of plasma TMAO in humans. TMAO was not associated with other plasma markers of cardiovascular disease, e.g. lipids or inflammatory cytokines. We first estimated TMAO heritability at 27%, indicating a moderate genetic influence. We used 1000 Genomes imputed data (n=626) to estimate genome-wide associations with TMAO levels, adjusting for age, sex, family relationships, and study site. The genome-wide study yielded one significant hit at the genome-wide level, located in an intergenic region on chromosome 4. We subsequently quantified epigenome-wide DNA methylation using the Illumina Infinium array on CD4+ T-cells. We tested for association of methylation loci with circulating TMAO (n=847), adjusting for age, sex, family relationships, and study site as the genome-wide study plus principal components capturing CD4+ T-cell purity. Upon adjusting for multiple testing, none of the epigenetic findings were statistically significant. CONCLUSIONS: Our findings contribute to the growing body of evidence suggesting that neither genetic nor epigenetic factors play a critical role in establishing circulating TMAO levels in humans. This work was funded by the American Heart Association (14CRP18060003, PI: Aslibekyan) and the National Institutes of Health (R01HL104135, PI: Arnett). Sí

The understanding of the genetic basis of neurological disorders has grown rapidly in the last two decades. Despite the genomic heterogeneity within African populations, large-scale candidate gene or linkage and exome studies are lacking. However, current knowledge on neurogenetics in African populations is limited and geographically very uneven. Isolated reports indicate the existence of autosomal dominant or recessive conditions incorporating cerebrovascular, movement, neuromuscular, seizure and motor neuron disorders in Africans. In addition, few African families with neurodegenerative disorders associated with dementia have been characterized in North, West and South Africa. The current insurgency in genomic research triggered by among others the Human Health and Heredity (H3) Africa Initiative indicates that there are unique opportunities to advance our knowledge and understanding of the influence of genomic variation on the pattern, presentations and prognosis of neurological disorders in Africa. These have enormous potential to unmask novel genes and molecular pathways germane to the neurobiology of brain disorders. It would facilitate the development of novel diagnostics, preventative and targeted treatments in the new paradigm of precision medicine. Nevertheless, it is crucial to strike a balance between effective traditional public health strategies and personalized genome based care. The translational barriers can be overcome through robust stakeholder engagement and sustainable multilevel, multigenerational and multidisciplinary capacity building and infrastructural development for genomic medicine in Africa.

BACKGROUND Low blood vitamin D concentration is a concern for people living in circumpolar regions, where sunlight is insufficient for vitamin D synthesis in winter months and the consumption of traditional dietary sources of vitamin D is decreasing. OBJECTIVE The objective was to characterize the effects of diet, genetic variation, and season on serum 25-hydroxycholecalciferol [25(OH)D3] concentrations in Yup'ik Alaska Native people living in rural southwest Alaska. METHODS This study was a cross-sectional design that assessed the associations of traditional diet (via a biomarker, the RBC δ(15)N value), age, gender, body mass index (BMI), community location, and genotype of select single nucleotide polymorphisms (SNPs) in cytochrome P450 family 2, subfamily R, peptide 1 (CYP2R1), 7-dehydrocholesterol reductase (DHCR7), and vitamin D binding protein (GC) with serum 25(OH)D3 concentrations in 743 Yup'ik male and female participants, aged 14-93 y, recruited between September 2009 and December 2013. RESULTS Yup'ik participants, on average, had adequate concentrations of serum 25(OH)D3 (31.1 ± 1.0 ng/mL). Variations in diet, BMI, age, gender, season of sample collection, and inland or coastal community geography were all significantly associated with serum 25(OH)D3 concentration. In models not adjusting for other covariates, age, diet, and seasonal effects explained 33.7%, 20.7%, and 9.8%, respectively, of variability in serum 25(OH)D3 concentrations. Of the 8 SNPs interrogated in CYP2R1 and DHCR7, only rs11023374 in CYP2R1 was significantly associated with serum 25(OH)D3, explaining 1.5% of variability. The GC haplotype explained an additional 2.8% of variability. Together, age, diet, gender, season of sample collection, BMI, geography of the community, and genotype at rs11023374 explained 52.5% of the variability in serum 25(OH)D3 concentrations. CONCLUSIONS Lower consumption of the traditional diet was associated with lower serum concentrations of 25(OH)D3. Younger adults and youth in this community may be at increased risk of adverse outcomes associated with vitamin D insufficiency compared with older members of the community, especially during seasons of low sunlight exposure, because of lower consumption of dietary sources of vitamin D.

Background Although highly heritable, few genes have been linked to spontaneous intracerebral hemorrhage (SICH), which does not currently have any evidence-based disease-modifying therapy. Individuals of African ancestry are especially susceptible to SICH, even more so for indigenous Africans. We systematically reviewed the genetic variants associated with SICH and examined opportunities for rapidly advancing SICH genomic research for precision medicine. Method We searched the National Human Genome Research Institute-European Bioinformatics Institute (NHGRI–EBI) Genome Wide Association Study (GWAS) catalog and PubMed for original research articles on genetic variants associated with SICH as of 15 June 2019 using the PRISMA guideline. Results Eight hundred and sixty-four articles were identified using pre-specified search criteria, of which 64 met the study inclusion criteria. Among eligible articles, only 9 utilized GWAS approach while the rest were candidate gene studies. Thirty-eight genetic loci were found to be variously associated with the risk of SICH, hematoma volume, functional outcome and mortality, out of which 8 were from GWAS including APOE, CR1, KCNK17, 1q22, CETP, STYK1, COL4A2 and 17p12. None of the studies included indigenous Africans. Conclusion Given this limited information on the genetic contributors to SICH, more genomic studies are needed to provide additional insights into the pathophysiology of SICH, and develop targeted preventive and therapeutic strategies. This call for additional investigation of the pathogenesis of SICH is likely to yield more discoveries in the unexplored indigenous African populations which also have a greater predilection.

The triglyceride (TG) response to a high-fat meal (postprandial lipemia, PPL) affects cardiovascular disease risk and is influenced by genes and environment. Genes involved in lipid metabolism have dominated genetic studies of PPL TG response. We sought to elucidate common genetic variants through a genome-wide association (GWA) study in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN).The GOLDN GWAS discovery sample consisted of 872 participants within families of European ancestry. Genotypes for 2,543,887 variants were measured or imputed from HapMap. Replication of our top results was performed in the Heredity and Phenotype Intervention (HAPI) Heart Study (n = 843). PPL TG response phenotypes were constructed from plasma TG measured at baseline (fasting, 0 hour), 3.5 and 6 hours after a high-fat meal, using a random coefficient regression model. Association analyses were adjusted for covariates and principal components, as necessary, in a linear mixed model using the kinship matrix; additional models further adjusted for fasting TG were also performed. Meta-analysis of the discovery and replication studies (n = 1715) was performed on the top SNPs from GOLDN.GOLDN revealed 111 suggestive (p1E-05) associations, with two SNPs meeting GWA significance level (p5E-08). Of the two significant SNPs, rs964184 demonstrated evidence of replication (p = 1.20E-03) in the HAPI Heart Study and in a joint analysis, was GWA significant (p = 1.26E-09). Rs964184 has been associated with fasting lipids (TG and HDL) and is near ZPR1 (formerly ZNF259), close to the APOA1/C3/A4/A5 cluster. This association was attenuated upon additional adjustment for fasting TG.This is the first report of a genome-wide significant association with replication for a novel phenotype, namely PPL TG response. Future investigation into response phenotypes is warranted using pathway analyses, or newer genetic technologies such as metabolomics.

Lipoprotein subfractions help discriminate cardiometabolic disease risk. Genetic loci validated as associating with lipoprotein measures do not account for a large proportion of the individual variation in lipoprotein measures. We hypothesized that DNA methylation levels across the genome contribute to interindividual variation in lipoprotein measures. Using data from participants of the Genetics of Lipid Lowering Drugs and Diet Network (n = 663 for discovery and n = 331 for replication stages, respectively), we conducted the first systematic screen of the genome to determine associations between methylation status at ∼470,000 cytosine-guanine dinucleotide (CpG) sites in CD4(+) T cells and 14 lipoprotein subfraction measures. We modeled associations between methylation at each CpG site and each lipoprotein measure separately using linear mixed models, adjusted for age, sex, study site, cell purity, and family structure. We identified two CpGs, both in the carnitine palmitoyltransferase-1A (CPT1A) gene, which reached significant levels of association with VLDL and LDL subfraction parameters in both discovery and replication phases (P < 1.1 × 10(-7) in the discovery phase, P < .004 in the replication phase, and P < 1.1 × 10(-12) in the full sample). CPT1A is regulated by PPARα, a ligand for drugs used to reduce CVD. Our associations between methylation in CPT1A and lipoprotein measures highlight the epigenetic role of this gene in metabolic dysfunction.

Background and aims Adiponectin is an adipose-secreted protein that has been linked to changes in insulin sensitivity, high-density lipoprotein cholesterol levels, and inflammatory patterns. Although fenofibrate therapy can raise adiponectin levels, treatment response is heterogeneous and heritable, suggesting a role for genetic mediators. This is the first genome-wide association study of fenofibrate effects on circulating adiponectin. Methods and results Plasma adiponectin was measured in participants of the Genetics of Lipid Lowering Drugs and Diet Network ( n = 793) before and after a 3-week daily treatment with 160 mg of fenofibrate. Associations between variants on the Affymetrix Genome-Wide Human SNP Array 6.0 and adiponectin were assessed using mixed linear models, adjusted for age, sex, site, and family. We observed a statistically significant ( P = 5 × 10 −8 ) association between rs2384207 in 12q24, a region previously linked to several metabolic traits, and the fenofibrate-induced change in circulating adiponectin. Additionally, our genome-wide analysis of baseline adiponectin levels replicated the previously reported association with CDH13 and suggested novel associations with markers near the PCK1, ZBP1, TMEM18, and SCUBE1 genes. The findings from the single marker tests were corroborated in gene-based analyses. Biological pathway analyses suggested a borderline significant association between the EGF receptor signaling pathway and baseline adiponectin levels. Conclusions We present preliminary evidence linking several biologically relevant genetic variants to adiponectin levels at baseline and in response to fenofibrate therapy. Our findings provide support for fine-mapping of the 12q24 region to investigate the shared biological mechanisms underlying levels of circulating adiponectin and susceptibility to metabolic disease.

Variants of carnitine palmitoyltransferase 1A (CPT1A), a key hepatic lipid oxidation enzyme, may influence how fatty acid oxidation contributes to obesity and metabolic outcomes. CPT1A is regulated by diet, suggesting interactions between gene variants and diet may influence outcomes. The objective of this study was to test the association of CPT1A variants with body composition and lipids, mediated by consumption of polyunsaturated fatty acids (PUFA). Obesity phenotypes and fasting lipids were measured in a cross-sectional sample of Yup'ik Eskimo individuals (n = 1141) from the Center of Alaska Native Health Research (CANHR) study. Twenty-eight tagging CPT1A SNPs were evaluated with outcomes of interest in regression models accounting for family structure. Several CPT1A polymorphisms were associated with HDL-cholesterol and obesity phenotypes. The P479L (rs80356779) variant was associated with all obesity-related traits and fasting HDL-cholesterol. Interestingly, the association of P479L with HDL-cholesterol was still significant after correcting for body mass index (BMI), percentage body fat (PBF), or waist circumference (WC). Our findings are consistent with the hypothesis that the L479 allele of the CPT1A P479L variant confers a selective advantage that is both cardioprotective (through increased HDL-cholesterol) and associated with reduced adiposity.

Laminins are large heterotrimeric glycoproteins found in basement membranes where they play an essential role in cell-matrix adhesion, migration, growth, and differentiation of various cell types. Previous work reported that a genetic variant located within the intron 1 of LAMA5 (rs659822) was associated with anthropometric traits and HDL-cholesterol levels in a cohort of premenopausal women. The present study aimed to investigate the effect of LAMA5 rs659822 on anthropometric traits, lipid profile, and fasting glucose levels in an Italian cohort of 667 healthy elderly subjects (aged 64-107years). We also tested for association between these traits and the single nucleotide polymorphism (SNP) rs13043313, which was previously shown to control variation in LAMA5 transcript abundance in the liver of Caucasians. In age- and gender-adjusted linear regression analyses, we did not find association of rs13043313 with any of the traits. However, under an additive model, the minor C-allele of LAMA5 rs659822 was associated with shorter stature (p = 0.007) and higher fasting glucose levels (p = 0.02). Moreover, subjects homozygous for the C-allele showed on average 6% and 10% lower total cholesterol (p = 0.034) and LDL-cholesterol (p = 0.016) levels, respectively, than those carrying at least one T allele, assuming a recessive model. Finally, in analyses stratified by age groups (age range 64-89 and 90-107 years), we found that the C-allele was additively associated with increased body weight (p = 0.018) in the age group 64-89 years, whereas no association was found in the age group 90-107 years. In conclusion, this study provides evidence that LAMA5 rs659822 regulates anthropometric and metabolic traits in elderly people. Future studies are warranted to replicate these findings in independent and larger populations and to investigate whether rs659822 is the causal variant responsible for the observed associations.

The purpose of the study was to estimate familial correlations and heritability to evaluate familial aggregation patterns of maxillary midline diastemas. The sample consisted of 30 extended families: 15 black, 14 white, and 1 mixed race. A single ascertainment scheme was adopted to collect the sample. Family data were collected with a 7-question survey. In all, the sample of 430 subjects consisted of 220 females, 210 males, 99 nuclear families, 534 sibling pairs, 422 avuncular pairs, 318 grandparent pairs, and 27 cousin pairs. Families were stratified by race to avoid any bias. The mixed-race family was excluded from the analysis. Data were analyzed using the program REGC in the Statistical Analysis for Genetic Epidemiology (S.A.G.E., Case Western Reserve University, Cleveland, Ohio) software. Heritability was found to be 0.32 +/- 0.14 in the white sample and 0.04 +/- 0.16 in the black sample. The preliminary results suggest a possible genetic basis for maxillary midline diastema and a greater role of environmental factors in the black sample than in the white sample.

SummaryThe transmission/disequilibrium (TD) test (TDT), proposed, by Spielman et al., for binary traits is a powerful method for detection of linkage between a marker locus and a disease locus, in the presence of allelic association. As a test for linkage disequilibrium, the TDT makes the assumption that any allelic association present is due to linkage. Allison proposed a series of TD-type tests for quantitative traits and calculated their power, assuming that the marker locus is the disease locus. All these tests assume that the observations are independent, and therefore they are applicable, as a test for linkage, only for nuclear-family data. In this report, we propose a regression-based TD-type test for linkage between a marker locus and a quantitative trait locus, using information on the parent-to-offspring transmission status of the associated allele at the marker locus. This method does not require independence of observations, thus allowing for analysis of pedigree data as well, and allows adjustment for covariates. We investigate the statistical power and validity of the test by simulating markers at various recombination fractions from the disease locus.