The influence of socioeconomic characteristics on active travel in US metropolitan areas and the contribution to health inequity.

Background: The prevalence of chronic disease in the US adult population varies across socioeconomic groups in the USA where approximately six in 10 adults have a chronic condition. Walking or cycling reduces the risk to many of these diseases and is influenced by the built environment, accessibility, and safety.

Methods: We performed multivariate logistic and linear regression on the Health-Oriented Transportation model parameters using the 2009 and 2017 US National Household Transportation surveys, restricted to adults in major metropolitan areas.

An Analysis of the Health Effects of Physical Activity due to Active Travel Policies in Rennes, France.

Background: Rennes, a midsize city in France, features many opportunities for active travel. City officials seek to increase walking and cycling by 2030 to improve public health. Physical inactivity, a leading risk factor for premature mortality around the globe, has been shown to be associated with many chronic diseases including heart disease, type 2 diabetes, and cancer.

The Health-Oriented Transportation Model: Estimating the health benefits of active transportation.

Introduction: Overdependence on gasoline-powered personal automobiles in industrialized urban settings has resulted in transportation behaviour that is detrimental to public health. Risk not only stems from an increase in air pollution, but also, and more significantly for wealthy nations, from a reduction in physical activity. Tools and models that demonstrate the magnitude of the health benefits of physical activity are needed to inform policies addressing the epidemic of physical inactivity and to help promote environmentally sustainable cities.

Mindfulness and Climate Change Action: A Feasibility Study.

Pro-environmental behaviors and the cultural shifts that can accompany these may offer solutions to the consequences of a changing climate. Mindfulness has been proposed as a strategy to initiate these types of behaviors. In 2017, we pilot-tested Mindful Climate Action (MCA), an eight-week adult education program that delivers energy use, climate change, and sustainability content in combination with training in mindfulness meditation, to 16 individuals living in Madison, WI.

A genome-wide study of inherited deletions identified two regions associated with nonsyndromic isolated oral clefts.

Background: DNA copy number variants play an important part in the development of common birth defects such as oral clefts. Individual patients with multiple birth defects (including oral clefts) have been shown to carry small and large chromosomal deletions.

Methods: We investigated the role of polymorphic copy number deletions by comparing transmission rates of deletions from parents to offspring in case-parent trios of European ancestry ascertained through a cleft proband with trios ascertained through a normal offspring.

Analytic power and sample size calculation for the genotypic transmission/disequilibrium test in case-parent trio studies.

Case-parent trio studies considering genotype data from children affected by a disease and their parents are frequently used to detect single nucleotide polymorphisms (SNPs) associated with disease. The most popular statistical tests for this study design are transmission/disequilibrium tests (TDTs). Several types of these tests have been developed, for example, procedures based on alleles or genotypes.

Detecting disease variants in case-parent trio studies using the bioconductor software package trio.

Case-parent trio studies are commonly employed in genetics to detect variants underlying common complex disease risk. Both commercial and freely available software suites for genetic data analysis usually contain methods for case-parent trio designs. A user might, however, experience limitations with these packages, which can include missing functionality to extend the software if a desired analysis has not been implemented, and the inability to programmatically capture all the software versions used for low-level processing and high-level inference of genomic data, a critical consideration in particular for high-throughput experiments.

Inferring rare disease risk variants based on exact probabilities of sharing by multiple affected relatives.

Motivation: Family-based designs are regaining popularity for genomic sequencing studies because they provide a way to test cosegregation with disease of variants that are too rare in the population to be tested individually in a conventional case-control study.

Results: Where only a few affected subjects per family are sequenced, the probability that any variant would be shared by all affected relatives-given it occurred in any one family member-provides evidence against the null hypothesis of a complete absence of linkage and association. A P-value can be obtained as the sum of the probabilities of sharing events as (or more) extreme in one or more families.

A genome-wide study of de novo deletions identifies a candidate locus for non-syndromic isolated cleft lip/palate risk.

Background: Copy number variants (CNVs) may play an important part in the development of common birth defects such as oral clefts, and individual patients with multiple birth defects (including clefts) have been shown to carry small and large chromosomal deletions. In this paper we investigate de novo deletions defined as DNA segments missing in an oral cleft proband but present in both unaffected parents. We compare de novo deletion frequencies in children of European ancestry with an isolated, non-syndromic oral cleft to frequencies in children of European ancestry from randomly sampled trios.

On multi-marker tests for association in case-control studies.

Genome-wide association studies (GWAs) have identified thousands of DNA loci associated with a variety of traits. Statistical inference is almost always based on single marker hypothesis tests of association and the respective p-values with Bonferroni correction. Since commercially available genomic arrays interrogate hundreds of thousands or even millions of loci simultaneously, many causal yet undetected loci are believed to exist because the conditional power to achieve a genome-wide significance level can be low, in particular for markers with small effect sizes and low minor allele frequencies and in studies with modest sample size.

LRRTM3 interacts with APP and BACE1 and has variants associating with late-onset Alzheimer's disease (LOAD).

Leucine rich repeat transmembrane protein 3 (LRRTM3) is member of a synaptic protein family. LRRTM3 is a nested gene within α-T catenin (CTNNA3) and resides at the linkage peak for late-onset Alzheimer's disease (LOAD) risk and plasma amyloid β (Aβ) levels. In-vitro knock-down of LRRTM3 was previously shown to decrease secreted Aβ, although the mechanism of this is unclear.

Fast detection of de novo copy number variants from SNP arrays for case-parent trios.

Background: In studies of case-parent trios, we define copy number variants (CNVs) in the offspring that differ from the parental copy numbers as de novo and of interest for their potential functional role in disease. Among the leading array-based methods for discovery of de novo CNVs in case-parent trios is the joint hidden Markov model (HMM) implemented in the PennCNV software. However, the computational demands of the joint HMM are substantial and the extent to which false positive identifications occur in case-parent trios has not been well described.

Gene expression levels as endophenotypes in genome-wide association studies of Alzheimer disease.

Background: Late-onset Alzheimer disease (LOAD) is a common disorder with a substantial genetic component. We postulate that many disease susceptibility variants act by altering gene expression levels.

Methods: We measured messenger RNA (mRNA) expression levels of 12 LOAD candidate genes in the cerebella of 200 subjects with LOAD.

Concordant association of insulin degrading enzyme gene (IDE) variants with IDE mRNA, Abeta, and Alzheimer's disease.

Background: The insulin-degrading enzyme gene (IDE) is a strong functional and positional candidate for late onset Alzheimer's disease (LOAD).

Methodology/principal Findings: We examined conserved regions of IDE and its 10 kb flanks in 269 AD cases and 252 controls thereby identifying 17 putative functional polymorphisms. These variants formed eleven haplotypes that were tagged with ten variants.

Genetic variation in PCDH11X is associated with susceptibility to late-onset Alzheimer's disease.

By analyzing late-onset Alzheimer's disease (LOAD) in a genome-wide association study (313,504 SNPs, three series, 844 cases and 1,255 controls) and evaluating the 25 SNPs with the most significant allelic association in four additional series (1,547 cases and 1,209 controls), we identified a SNP (rs5984894) on Xq21.3 in PCDH11X that is strongly associated with LOAD in individuals of European descent from the United States. Analysis of rs5984894 by multivariable logistic regression adjusted for sex gave global P values of 5.

Sex-dependent association of a common low-density lipoprotein receptor polymorphism with RNA splicing efficiency in the brain and Alzheimer's disease.

Since apoE allele status is the predominant Alzheimer's disease (AD) genetic risk factor, functional single nucleotide polymorphisms (SNPs) in brain apoE receptors represent excellent candidates for association with AD. Recently, we identified a SNP, rs688, as modulating the splicing efficiency of low-density lipoprotein receptor (LDLR) exon 12 in female human liver and in minigene-transfected HepG2 cells. Moreover, the rs688T minor allele was associated with significantly higher LDL and total cholesterol in women within the Framingham Offspring Study cohort.

Fine mapping of the alpha-T catenin gene to a quantitative trait locus on chromosome 10 in late-onset Alzheimer's disease pedigrees.

Using plasma amyloid beta protein (Abeta42) levels as an intermediate, quantitative phenotype for late onset Alzheimer's disease (LOAD), we previously obtained significant linkage at approximately 80 cM on chromosome 10. Linkage to the same region was obtained independently in a study of affected LOAD sib-pairs. Together, these two studies provide strong evidence for a novel LOAD locus on chromosome 10 that acts to increase Abeta42.