Missing heritability of complex diseases: Enlightenment by genetic variants from intermediate phenotypes

Diseases of complex origin have a component of quantitative genetics that contributes to their susceptibility and phenotypic variability. However, after several studies, a major part of the genetic component of complex phenotypes has still not been found, a situation known as “missing heritability.” Although there have been many hypotheses put forward to explain the reasons for the missing heritability, its definitive causes remain unknown. Complex diseases are caused by multiple intermediate phenotypes involved in their pathogenesis and, very often, each one of these intermediate phenotypes also has a component of quantitative inheritance. Here we propose that at least part of the missing heritability can be explained by the genetic component of intermediate phenotypes that is not detectable at the level of the main complex trait. At the same time, the identification of the genetic component of intermediate phenotypes provides an opportunity to identify part of the missing heritability of complex diseases.     

Environment-sensitive epigenetics and the heritability of complex diseases

Genome-wide association studies have thus far failed to explain the observed heritability of complex human diseases. This is referred to as the "missing heritability" problem. However, these analyses have usually neglected to consider a role for epigenetic variation, which has been associated with many human diseases. We extend models of epigenetic inheritance to investigate whether environment-sensitive epigenetic modifications of DNA might explain observed patterns of familial aggregation. We find that variation in epigenetic state and environmental state can result in highly heritable phenotypes through a combination of epigenetic and environmental inheritance. These two inheritance processes together can produce familial covariances significantly higher than those predicted by models of purely epigenetic inheritance and similar to those expected from genetic effects. The results suggest that epigenetic variation, inherited both directly and through shared environmental effects, may make a key contribution to the missing heritability.     

Missing heritability of Wilson disease: a search for the uncharacterized mutations

Mammalian Genome - Wilson disease (WD), a copper metabolism disorder caused by mutations in ATP7B, manifests heterogeneous clinical features. Interestingly, in a fraction of clinically diagnosed WD...     

Reducing the exome search space for Mendelian diseases using genetic linkage analysis of exome genotypes

Many exome sequencing studies of Mendelian disorders fail to optimally exploit family information. Classical genetic linkage analysis is an effective method for eliminating a large fraction of the candidate causal variants discovered, even in small families that lack a unique linkage peak. We demonstrate that accurate genetic linkage mapping can be performed using SNP genotypes extracted from exome data, removing the need for separate array-based genotyping. We provide software to facilitate such analyses.     

外显子组测序在人类疾病中的应用

据估计,约85%的人类遗传变异集中在蛋白编码区,因此对全部的蛋白编码区（外显子组）进行重测序,可以快速、有效地鉴定人类疾病遗传变异。以往鉴定孟德尔遗传病的致病基因多采用连锁分析结合候选定位克隆的方法,不仅耗时长,而且成功率低。2009年,科学家第一次应用外显子组测序在4名弗里曼谢尔登综合征（常染色体显性遗传病）中发现了位于MYH3中的点突变,显示出外显子组测序在孟德尔遗传病致病基因鉴定中的强大功效。就复杂疾病而言,传统的关联研究,包括全基因组关联研究（GWAS）,虽然鉴定了大量的常见变异,但对低频变异和罕见变异的检测能力十分有限;深度测序的发展为解决上述问题提供了良好的契机。本文就外显子组测序在人类疾病中的应用作一简要综述。     

外显子组测序技术在人类疾病研究中的应用

外显子组测序是针对基因组中的蛋白质编码区,靶向富集外显子区域测序,以发现疾病相关遗传变异的技术。该技术近年越来越多地应用于发现人类基因组低频变异、鉴定单基因遗传病致病基因和肿瘤等复杂疾病易感基因研究,成为人类疾病相关变异研究的重要工具。综述了外显子组测序技术的基本原理及其在人类疾病相关基因研究中的应用。     

14种多基因、疑为多基因遗传病的遗传率研究

本文采用Falconer法和其修正法计算了14种多基因疾病的遗传率（h2）。研究结果表明：脑性瘫痪、先天性耳廓畸形、原因不明精神发育迟滞、脊柱侧弯或瑚突有明显遗传倾向（h2>0.75）; 共转性内斜视、唇裂±腭裂、先天性髋关节关节脱位、多指（趾）症、腹股沟斜疝、银屑病（牛皮癣）及原发性癫痫有遗传倾向（0.60< h2<0.75）; 而共转性外斜视、精索静脉曲张、隐睾症以及先天性心脏病（各型）受遗传因素的作用相对较小（h2<0.60）。Abstract: An epidemiologic survey of genetic diseases was carried out in general population from 11 areas, 42 survey sites, 126876 people of Sichuan. With the stratified cluster random samping method, 150 kinds ofgenetic diseases were found according to the diagnostic strandard. And the heritabilities of 14 kinds of polygenic or polygenic-doubted diseases were estimated. The results showed that the contribution of genetic factors to aetiology is greater in cerebral paisy, congenital ear deformity, mental retardation of unknown actiology and scoliosis (h2>0.75). The congenital of genetic factors is moderate in con.comitant esotropia, cleft lip±cleft palate, congenital dislocation of the hip, Polydactyly, inguinal oblique hernia, psoriasis as well as idiopatic epilepsy (0.60< h2<0.75). The contribution of genetic factors is relatively little in concomitant exotropia, varicocele, enorchia and congenital heart disease (various types)( h2<0.60).     

The complete sequence of the mouse skeletal alpha-actin gene reveals several conserved and inverted repeat sequences outside of the protein-coding region.

The complete nucleotide sequence of a genomic clone encoding the mouse skeletal alpha-actin gene has been determined. This single-copy gene codes for a protein identical in primary sequence to the rabbit skeletal alpha-actin. It has a large intron in the 5'-untranslated region 12 nucleotides upstream from the initiator ATG and five small introns in the coding region at codons specifying amino acids 41/42, 150, 204, 267, and 327/328. These intron positions are identical to those for the corresponding genes of chickens and rats. Similar to other skeletal alpha-actin genes, the nucleotide sequence codes for two amino acids, Met-Cys, preceding the known N-terminal Asp of the mature protein. Comparison of the nucleotide sequences of rat, mouse, chicken, and human skeletal muscle alpha-actin genes reveals conserved sequences (some not previously noted) outside of the protein-coding region. Furthermore, several inverted repeat sequences, partially within these conserved regions, have been identified. These sequences are not present in the vertebrate cytoskeletal beta-actin genes. The strong conservation of the inverted repeat sequences suggests that they may have a role in the tissue-specific expression of skeletal alpha-actin genes.     

Genetic mapping and exome sequencing identify variants associated with five novel diseases

The Clinic for Special Children (CSC) has integrated biochemical and molecular methods into a rural pediatric practice serving Old Order Amish and Mennonite (Plain) children. Among the Plain people, we have used single nucleotide polymorphism (SNP) microarrays to genetically map recessive disorders to large autozygous haplotype blocks (mean = 4.4 Mb) that contain many genes (mean = 79). For some, uninformative mapping or large gene lists preclude disease-gene identification by Sanger sequencing. Seven such conditions were selected for exome sequencing at the Broad Institute; all had been previously mapped at the CSC using low density SNP microarrays coupled with autozygosity and linkage analyses. Using between 1 and 5 patient samples per disorder, we identified sequence variants in the known disease-causing genes SLC6A3 and FLVCR1, and present evidence to strongly support the pathogenicity of variants identified in TUBGCP6, BRAT1, SNIP1, CRADD, and HARS. Our results reveal the power of coupling new genotyping technologies to population-specific genetic knowledge and robust clinical data.     

Bilirubin and the risk of common non-hepatic diseases

Bilirubin is a potent antioxidant but can be toxic at high concentrations. This article critically reviews the reported relationships of plasma bilirubin levels to the severity and/or incidence of various common non-hepatic diseases. Plasma bilirubin levels are reportedly negatively related to the risk of atherosclerotic diseases, cancers, demyelinating neuropathies and seasonal affective disorder. By contrast, the incidence and severity of schizophrenia are increased by elevated bilirubin levels. The data strongly suggest that the level of plasma bilirubin should be considered as a risk factor for several common non-hepatic diseases. Additional studies are needed to clarify the mechanisms of this influence, which are thought to be related to unconjugated bilirubin counteracting the oxidative stress underlying these disorders.     

A comprehensive framework for prioritizing variants in exome sequencing studies of Mendelian diseases

Exome sequencing strategy is promising for finding novel mutations of human monogenic disorders. However, pinpointing the casual mutation in a small number of samples is still a big challenge. Here, we propose a three-level filtration and prioritization framework to identify the casual mutation(s) in exome sequencing studies. This efficient and comprehensive framework successfully narrowed down whole exome variants to very small numbers of candidate variants in the proof-of-concept examples. The proposed framework, implemented in a user-friendly software package, named KGGSeq (http://statgenpro.psychiatry.hku.hk/kggseq), will play a very useful role in exome sequencing-based discovery of human Mendelian disease genes.     

Estimation of heritability by offspring-parent regression when observations do not have a common mean

Summary Offspring-parent regression is a simple method for estimating heritability. This method yields unbiased estimates even when parents are selected. The usual model in offspring-parent regression assumes that observations have the same mean. This assumption, however, is not met in many situations. A method for estimating heritability by offspring-parent regression when observations do not have a common mean is presented. The estimator is distributed as a multiple of a t random variable centered at its parametric value and is unbiased even when the parents are selected. When observations have a common mean, the method reduces to the usual regression estimator.     

Population genetics models of common diseases

The number and frequency of susceptibility alleles for common diseases are important factors to consider in the efficient design of disease association studies. These quantities are the results of the joint effects of mutation, genetic drift and selection. Hence, population genetics models, informed by empirical knowledge about patterns of disease variation, can be used to make predictions about the allelic architecture of common disease susceptibility and to gain an overall understanding about the evolutionary origins of such diseases. Equilibrium models and empirical studies suggest a role for both rare and common variants. In addition, increasing evidence points to changes in selective pressures on susceptibility genes for common diseases; these findings are likely to form the basis for further modeling studies.     

Calcium-sensitive ROS-GC1 signaling outside of photoreceptors: A common theme

Until now, ROS-GC1 signal transduction system was thought to be exclusive to photoreceptors in the retina. Two recent reports, however, now show that this is not the case. In one, the ROS-GC1 signal transduction system has been identified and characterized in pinealocyte neurons. This signaling is modulated by norepinephrine. However, the response of the individual pinealocyte neuron to the norepinephrine signal depends on whether the GCAP1-linked (results in hyperpolarization) or S100-linked (results in depolarization) pathway is operational in the pinealocyte. The GCAP1-linked pathway results in hyperpolarization, while the S100-linked pathway, in depolarization. The two pathways are mutually exclusive. In the other report, the calcium-modulated ROS-GC1:GCAP1 signaling system has been discovered in mitral cells of the olfactory bulb. These findings raise the possibility that a common theme of calcium-modulated ROS-GC signaling may be utilized in a wide variety of neurosensory cells. This idea is also supported from evolutionary and functional perspectives.