Iris van Rooij

Smoking, Genetic Polymorphisms in Biotransformation Enzymes, and Nonsyndromic Oral Clefting: A Gene-environment Interaction

The importance of maternal smoking in the pathogenesis of oral facial clefts is not clear. Susceptibility to cigarette smoke depends on biotransformation of the toxic compounds by mother and embryo. In a population-based case-control study, we investigated the effects of maternal smoking during the first pregnancy trimester and the interaction with polymorphisms in the biotransformation enzymes cytochrome P450 1A1 (CYP1A1) and glutathione S-transferase theta 1–1 (GSTT1) on the risk of nonsyndromic oral clefting in the offspring. We recruited 113 infants with nonsyndromic oral clefts and their mothers, as well as 104 control infants and their mothers. Maternal smoking habits were collected regarding the period 3 months before through 3 months after conception. Buccal swabs were taken from mothers and infants for genetic analysis. Maternal smoking was not strongly associated with oral clefting (odds ratio = 1.1; 95% confidence interval = 0.6–2.2), nor were CYP1A1 and GSTT1 polymorphisms. Mothers who smoked and carried the GSTT1-null genotype, however, had an increased risk for having a child with oral clefting compared with nonsmokers with the wild type genotype (odds ratio = 3.2; 95% confidence interval = 0.9–11.6). The risk was almost five times greater (odds ratio = 4.9; 95% confidence interval = 0.7–36.9) in mothers and infants both having the GSTT1-null genotype compared with both having the wild genotype. There was no interaction between CYP1A1 and maternal smoking in relation to oral clefting.

Common variants in DGKK are strongly associated with risk of hypospadias

Hypospadias is a common congenital malformation of the male external genitalia. We performed a genome-wide association study using pooled DNA from 436 individuals with hypospadias (cases) and 494 controls of European descent and selected the highest ranked SNPs for individual genotyping in the discovery sample, an additional Dutch sample of 133 cases and their parents, and a Swedish series of 266 cases and 402 controls. Individual genotyping of two SNPs (rs1934179 and rs7063116) in DGKK, encoding diacylglycerol kinase κ, produced compelling evidence for association with hypospadias in the discovery sample (allele-specific odds ratio (OR) = 2.5, P = 2.5 × 10−11 and OR = 2.3, P = 2.9 × 10−9, respectively) and in the Dutch (OR = 3.9, P = 2.4 × 10−5 and OR = 3.8, P = 3.4 × 10−5) and Swedish (OR = 2.5, P = 2.6 × 10−8 and OR = 2.2, P = 2.7 × 10−6) replication samples. Expression studies showed expression of DGKK in preputial tissue of cases and controls, which was lower in carriers of the risk allele of rs1934179 (P = 0.047). We propose DGKK as a major risk gene for hypospadias.

Whole-exome resequencing reveals recessive mutations in TRAP1 in individuals with CAKUT and VACTERL association

Congenital abnormalities of the kidney and urinary tract (CAKUT) account for approximately half of children with chronic kidney disease and they are the most frequent cause of end-stage renal disease in children in the US. However, its genetic etiology remains mostly elusive. VACTERL association is a rare disorder that involves congenital abnormalities in multiple organs including the kidney and urinary tract in up to 60% of the cases. By homozygosity mapping and whole exome resequencing combined with high-throughput mutation analysis by array-based multiplex PCR and next-generation sequencing, we identified recessive mutations in the gene TNF receptor-associated protein 1 (TRAP1) in two families with isolated CAKUT and three families with VACTERL association. TRAP1 is a heat shock protein 90-related mitochondrial chaperone possibly involved in antiapoptotic and endoplasmic reticulum-stress signaling. Trap1 is expressed in renal epithelia of developing mouse kidney E13.5 and in the kidney of adult rats, most prominently in proximal tubules and in thick medullary ascending limbs of Henle’s loop. Thus, we identified mutations in TRAP1 as highly likely causing CAKUT or CAKUT in VACTERL association.

Genome-wide association analyses identify variants in developmental genes associated with hypospadias

Hypospadias is a common congenital condition in boys in which the urethra opens on the underside of the penis. We performed a genome-wide association study on 1,006 surgery-confirmed hypospadias cases and 5,486 controls from Denmark. After replication genotyping of an additional 1,972 cases and 1,812 controls from Denmark, the Netherlands and Sweden, 18 genomic regions showed independent association with P < 5 × 10−8. Together, these loci explain 9% of the liability to developing this condition. Several of the identified regions harbor genes with key roles in embryonic development (including HOXA4, IRX5, IRX6 and EYA1). Subsequent pathway analysis with GRAIL and DEPICT provided additional insight into possible genetic mechanisms causing hypospadias.

Understanding motor resonance

The discovery of mirror neurons in monkeys, and the finding of motor activity during action observation in humans are generally regarded to support motor theories of action understanding. These theories take motor resonance to be essential in the understanding of observed actions and the inference of action goals. However, the notions of “resonance,” “action understanding,” and “action goal” appear to be used ambiguously in the literature. A survey of the literature on mirror neurons and motor resonance yields two different interpretations of the term “resonance,” three different interpretations of action understanding, and again three different interpretations of what the goal of an action is. This entails that, unless it is specified what interpretation is used, the meaning of any statement about the relation between these concepts can differ to a great extent. By discussing an experiment we will show that more precise definitions and use of the concepts will allow for better assessments of motor theories of action understanding and hence a more fruitful scientific debate. Lastly, we will provide an example of how the discussed experimental setup could be adapted to test other interpretations of the concepts.

The role of frequency information and teleological reasoning in infants' and adults' action prediction

This study investigates the contribution of frequency learning and teleological reasoning to action prediction in 9-month-old infants and adults. Participants observed how an agent repeatedly walked to a goal while taking the longer of 2 possible paths, as the shorter and more efficient path was impassable. In the subsequent test phase, both paths were passable. In the 1st test trial, infants and adults anticipated the agent to take the longer path. Unlike adults, infants kept anticipating movements to the longer path even after observing that the agent now took the more efficient path, indicating that the frequency of previous observations dominates action prediction. These results provide evidence, contrary to existing claims in the developmental literature, that frequency learning underlies action prediction in infancy, whereas teleological reasoning might gain importance later on in life.

Myo‐inositol, glucose and zinc status as risk factors for non‐syndromic cleft lip with or without cleft palate in offspring: a case–control study

Objective  To investigate myo‐inositol, glucose and zinc status in mothers and their infants on cleft lip with or without cleft palate risk (CLP).

Convex hull and tour crossings in the Euclidean traveling salesperson problem: Implications for human performance studies

Recently there has been growing interest among psychologists in human performance on the Euclidean traveling salesperson problem (E-TSP). A debate has been initiated on what strategy people use in solving visually presented E-TSP instances. The most prominent hypothesis is the convex-hull hypothesis, originally proposed by MacGregor and Ormerod (1996). We argue that, in the literature so far, there is no evidence for this hypothesis. Alternatively we propose and motivate the hypothesis that people aim at avoiding crossings.

Can there be such a thing as embodied embedded cognitive neuroscience

Contemporary cognitive neuroscience, for the most part, aims to figure out how cognitive processes are realized in the brain. This research goal betrays the fields commitment to the philosophical position that cognizing is something that the brain does. Since the 1990s, philosophers and cognitive scientists have started to question this position, arguing that the brain constitutes only one of several contributing factors to cognition, the other factors being the body and the world. This latter position we refer to as embodied embedded cognition (EEC). Although cognitive neurosciences research practice and EEC do not seem to fit well together at present, it is pertinent to ask if a variant of cognitive neuroscience can be developed that sets itself research goals that are more congenial to the EEC view. In this paper we investigate this possibility. We put forth a new guiding metaphor of the role of the brain in cognitive behavior to replace the current cognitivist metaphor of the brain as an information-processing device. We also identify a research agenda that naturally arises from our metaphor. In this way we hope to provide an impetus for cognitive neuroscientists to pursue an EEC-inspired research program.

Maternal and paternal risk factors for anorectal malformations: a Dutch case-control study.

BACKGROUND Anorectal malformations (ARM) are major congenital malformations that usually require a multitude of surgical procedures at a very early age and have a large impact on the lives of patients and their parents. The causes of ARM are still largely unknown, but they are assumed to have a multifactorial etiology. A few studies focused on environmental risk factors, but evidence is still scarce. METHODS In this Dutch case-control study (1996-2008), we investigated the role of maternal and paternal risk factors in the etiology of ARM. Parents of 85 ARM cases and 650 controls filled in a questionnaire. Controls were children treated with ear ventilation tubes. RESULTS A higher occurrence of fever during the first trimester of pregnancy was found for case mothers compared to control mothers (odds ratio [OR], 5.1; 95% Confidence Interval [CI], 0.9, 28.1). Maternal occupational exposure to industrial cleaning agents and solvents increased the risk of ARM three times (OR, 2.9; 95% CI, 0.9, 9.3). Overweight (Body Mass Index [BMI] > or = 25 kg/m(2)) before pregnancy also seemed to be associated with ARM (OR, 1.8; 95% CI, 1.1, 2.8), as well as maternal multivitamin use during pregnancy (OR, 1.6; 95% CI, 1.0, 2.7), paternal smoking (OR, 1.8; 95% CI, 1.1, 2.9), and paternal occupational exposure to exhaust fumes (OR, 1.9; 95% CI, 1.0, 3.6). Reported ARM in at least one first- or second-degree family member greatly increased the risk of having a child with an ARM (OR, 40.3; 95% CI, 4.8, 342.8). CONCLUSIONS This study revealed potential risk factors for ARM, including fever during pregnancy, maternal overweight, use of multivitamins, paternal smoking, and occupational exposures, but a familial component seems important as well.