Neural networks for genetic epidemiology: past, present, and future

During the past two decades, the field of human genetics has experienced an information explosion. The completion of the human genome project and the development of high throughput SNP technologies have created a wealth of data; however, the analysis and interpretation of these data have created a research bottleneck. While technology facilitates the measurement of hundreds or thousands of genes, statistical and computational methodologies are lacking for the analysis of these data. New statistical methods and variable selection strategies must be explored for identifying disease susceptibility genes for common, complex diseases. Neural networks (NN) are a class of pattern recognition methods that have been successfully implemented for data mining and prediction in a variety of fields. The application of NN for statistical genetics studies is an active area of research. Neural networks have been applied in both linkage and association analysis for the identification of disease susceptibility genes

Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility

Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel NaV1.5, susceptibility genes remain largely unknown. Here we performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls, and identified 21 association signals at 12 loci (10 new). Single nucleotide polymorphism (SNP)-heritability estimates indicate a strong polygenic influence. Polygenic risk score analyses based on the 21 susceptibility variants demonstrate varying cumulative contribution of common risk alleles among different patient subgroups, as well as genetic associations with cardiac electrical traits and disorders in the general population. The predominance of cardiac transcription factor loci indicates that transcriptional regulation is a key feature of BrS pathogenesis. Furthermore, functional studies conducted on MAPRE2, encoding the microtubule plus-end binding protein EB2, point to microtubule-related trafficking effects on NaV1.5 expression as a new underlying molecular mechanism. Taken together, these findings broaden our understanding of the genetic architecture of BrS and provide new insights into its molecular underpinnings

S81 L and G170R mutations causing Primary Hyperoxaluria Type I in homozygosis and heterozygosis: an example of positive interallelic complementation.

Primary Hyperoxaluria type I (PH1) is a rare disease due to the deficit of peroxisomal alanine:glyoxylate aminotransferase (AGT), a homodimeric pyridoxal-5'-phosphate (PLP) enzyme present in humans as major (Ma) and minor (Mi) allele. PH1-causing mutations are mostly missense identified in both homozygous and compound heterozygous patients. Until now, the pathogenesis of PH1 has been only studied by approaches mimicking homozygous patients, whereas the molecular aspects of the genotype-enzymatic-clinical phenotype relationship in compound heterozygous patients are completely unknown. Here, for the first time, we elucidate the enzymatic phenotype linked to the S81L mutation on AGT-Ma, relative to a PLP-binding residue, and how it changes when the most common mutation G170R on AGT-Mi, known to cause AGT mistargeting without affecting the enzyme functionality, is present in the second allele. By using a bicistronic eukaryotic expression vector, we demonstrate that (i) S81L-Ma is mainly in its apo-form and has a significant peroxisomal localization and (ii) S81L and G170R monomers interact giving rise to the G170R-Mi/S81L-Ma holo-form, which is imported into peroxisomes and exhibits an enhanced functionality with respect to the parental enzymes. These data, integrated with the biochemical features of the heterodimer and the homodimeric counterparts in their purified recombinant form, (i) highlight the molecular basis of the pathogenicity of S81L-Ma and (ii) provide evidence for a positive interallelic complementation between the S81L and G170R monomers. Our study represents a valid approach to investigate the molecular pathogenesis of PH1 in compound heterozygous patients

Primary hyperoxaluria: report of an Italian family with clear sex conditioned penetrance

We report the clinical and genetic study of a primary hyperoxaluria type I (PH1) family with two sisters homozygous for p.Gly170Arg who are still asymptomatic at age 29 and 35, and two brothers, also homozygous for the same mutation, who are affected since age 27 and 30. The clear sex difference observed in this family and in others reported in the literature fits well with the prevalence of males over females in the Italian registry. In the KO model of PH1, only male mice develop renal stones, suggesting that the sex difference may affect both oxalate production and stone formation. A likely mechanism is the sex-related expression of glycolate oxidase shown in experimental animals. The stable isotope method recently developed by Huidekoper and van Woerden for in vivo assessment of the endogenous oxalate production could help to clarify the issue in humans

Influence of Bacillus Calmette-Guerin vaccination at birth and 2 months old age on the peripheral blood T-cell subpopulations [gamma/delta (gammadelta) and alpha-beta (alphabeta) T cell]

The neonatal immune system is immature and may be affected by Bacillus Calmette-Guerin (BCG) vaccine. We investigated the influence of BCG given at two different ages on the peripheral blood (PB) T-cell subpopulations. Forty full term healthy newborns were randomly chosen. Twenty of them were vaccinated with BCG at birth (group 1) and the remaining at the age of 2 months (group II). The cell analysis were carried out before (pre-BCGI and pre-BCGII), and 2 months after (post-BCGI and post-BCGII) the vaccination. The analysis of the gamma/delta and alpha/beta T-cell receptor (TCR) antigens was done by two-colour flowcytometer. The purified protein derivative (PPD) response was investigated 2 months after vaccination. The results showed that although T-cell (TCR+ cell) counts showed no difference in PB before and after vaccination in both study groups, the total lymphocyte and non-T cell (TCR- cell) populations increased significantly whereas alpha beta T-cell population significantly decreased after vaccination. On the contrary, gamma delta T-cell counts in PB increased significantly 2 months after vaccination in group I but not in group II. Total lymphocyte and non-T cell counts in vaccinated infants at 2 months of age (post-BCGI) were significantly higher than in unvaccinated infants of the same age whereas alpha beta T-cell count in vaccinated infants was significantly low. However, total T-cell and gamma delta T-cell counts showed no difference. PPD positivity was similar in both study groups (61% in group I, 66% in group II). Neither alpha beta T- nor gamma delta T-cell counts were different in PPD positive and PPD negative infants. Our study shows that BCG causes marked quantitative changes in the PB T-cell subpopulations in young infants