Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

Hundreds of variants clustered in genomic loci and biological pathways affect human height

https://n.neurology.org/content/neurology/62/11/2146.full.pdf

LGI1 mutations in autosomal dominant partial epilepsy with auditory features

Statistical Genetics: Gene Mapping Through Linkage and Association

Human mesial temporal lobe epilepsies (MTLE)are the most frequent form of partial epilepsies and display frequent pharmacoresistance The molecular alterations underlying human MTLE remain poorly understood A two- step transcriptional analysis consisting in cDNA microarray experiments followed by quantitative RT- PCR validations was performed Because the entorhinal cortex (EC) plays an important role in the pathophysiology of the MTLE and usually discloses no detectable or little cell loss, resected EC and each corresponding lateral temporal neocortex (LTC) of MTLE patients were used as the source of disease- associated and control RNAs, respectively Six genes encoding (i) a serotonin receptor (HTR2A) and a neuropeptide Y receptor type I (NPYIR), (ii) a protein (FHL2) associating with the KCNEI (minK) potassium channel subunit and with presenilin- 2 and (iii) three immune system- related proteins (C3, HLA- DR- γ and CD99), were found consistently downregulated or upregulated in the EC of MTLE patients as compared with non- epileptic autopsy controls Quantitative western blot analyses confirmed decreased expression of NPYIR in all eight MTLE patients tested Immunohistochemistry experiments revealed the existence of a perivascular infiltration of C3 positive leucocytes and/or detected membrane attack complexes on a subset of neurons, within the EC of nine out of eleven MTLE patients To summarize, a large- scale microarray expression study on the EC of MTLE patients led to the identification of six candidate genes for human MTLE pathophysiology Altered expression of NPYIR and C3 was also demonstrated at the protein level Overall, our data indicate that local dysregulation of the neurotransmission and complement systems in the EC is a frequent event in human MTLE

Large-scale expression study of human mesial temporal lobe epilepsy: Evidence for dysregulation of the neurotransmission and complement systems in the entorhinal cortex

Autosomal dominant epilepsy with febrile seizures plus

This thesis discusses four studies, looking for genetic determinants of common epilepsies: 1) A genome-wide association study (GWAS) of partial epilepsies (PE), which was the first published GWAS in the field of epilepsy (Chapter 4) 2) A GWAS of mesial temporal lobe epilepsy (MTLE) with hippocampal sclerosis (HS) (Chapter 5) 3) A case series of patients with refractory MTLE, operated and found to have large microdeletions at 16p1311, 15q112 and others (Chapter 6) 4) A clinical, genetic and neuropathologic study of a series of patients with Dravet syndrome (DS), diagnosed as adults, including genotype-phenotype correlation analysis (Chapter 7) The main findings include: 1) The GWAS of PE has not yielded any genome-wide significant association with common genetic variants, possibly because of insufficient power and phenotypical heterogeneity It is, however, a strong foundation for further studies, illustrating the feasibility of large multicentre GWAS in the epilepsies (Chapter 4) 2) The GWAS of MTLEHS yielded a borderline genome-wide statistically significant association with three common genetic variants close or intronic to the SCN1A gene, especially in MTLEHS with antecedents of childhood febrile seizures (Chapter 5) 3) Large microdeletions at 16p1311 and others were found in patients with MTLEHS and not only in idiopathic non-lesional epilepsies Good outcome after resective epilepsy surgery is possible in “typical” MTLEHS even with large microdeletions (Chapter 6) 4) The identification of a cohort of adults with DS, not diagnosed as children, allowed the description of long-term evolution through adulthood and recognition of clinical features shared later in the evolution Over sixty percent had SCN1A mutations Missense mutations were more frequent in patients who survived through adulthood, with truncating mutations and large deletions only found in those who died in early childhood Medication changes after diagnosis led in some cases to better seizure control, cognition and quality of life Further evidence for DS as encephalopathy came from post mortem histopathology, with no neuronal loss found in cerebral cortex or hippocampus

Genetic studies of the common epilepsies: genome-wide association studies in the partial epilepsies

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Genetic studies of the common epilepsies: genome-wide association studies in the partial epilepsies