Genome-wide association studies have identified hundreds of genetic variants associated with complex human diseases and traits, and have provided valuable insights into their genetic architecture. Most variants identified so far confer relatively small increments in risk, and explain only a small proportion of familial clustering, leading many to question how the remaining, 'missing' heritability can be explained. Here we examine potential sources of missing heritability and propose research strategies, including and extending beyond current genome-wide association approaches, to illuminate the genetics of complex diseases and enhance its potential to enable effective disease prevention or treatment.

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Finding the missing heritability of complex diseases

Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia.

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Biological insights from 108 schizophrenia-associated genetic loci

Schizophrenia is a severe mental disorder with a lifetime risk of about 1%, characterized by hallucinations, delusions and cognitive deficits, with heritability estimated at up to 80%(1,2). We performed a genome-wide association study of 3,322 European individuals with schizophrenia and 3,587 controls. Here we show, using two analytic approaches, the extent to which common genetic variation underlies the risk of schizophrenia. First, we implicate the major histocompatibility complex. Second, we provide molecular genetic evidence for a substantial polygenic component to the risk of schizophrenia involving thousands of common alleles of very small effect. We show that this component also contributes to the risk of bipolar disorder, but not to several non-psychiatric diseases.

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Common polygenic variation contributes to risk of schizophrenia and bipolar disorder

Age-related macular degeneration (AMD) is a major cause of blindness in the elderly. We report a genome-wide screen of 96 cases and 50 controls for polymorphisms associated with AMD. Among 116,204 single-nucleotide polymorphisms genotyped, an intronic and common variant in the complement factor H gene ( CFH ) is strongly associated with AMD (nominal P value -7 ). In individuals homozygous for the risk allele, the likelihood of AMD is increased by a factor of 7.4 (95% confidence interval 2.9 to 19). Resequencing revealed a polymorphism in linkage disequilibrium with the risk allele representing a tyrosine-histidine change at amino acid 402. This polymorphism is in a region of CFH that binds heparin and C-reactive protein. The CFH gene is located on chromosome 1 in a region repeatedly linked to AMD in family-based studies.

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Complement Factor H Polymorphism in Age-Related Macular Degeneration

Both polygenicity (many small genetic effects) and confounding biases, such as cryptic relatedness and population stratification, can yield an inflated distribution of test statistics in genome-wide association studies (GWAS). However, current methods cannot distinguish between inflation from a true polygenic signal and bias. We have developed an approach, LD Score regression, that quantifies the contribution of each by examining the relationship between test statistics and linkage disequilibrium (LD). The LD Score regression intercept can be used to estimate a more powerful and accurate correction factor than genomic control. We find strong evidence that polygenicity accounts for the majority of the inflation in test statistics in many GWAS of large sample size.

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LD score regression distinguishes confounding from polygenicity in genome-wide association studies :

A Discordant Sib–Pair Linkage Analysis of Age–Related Macular Degeneration

Background:Age-related macular degeneration (AMD) is the leading cause of visual impairment and blindness among older adults in the United States and throughout the developed world. Etiological research implicates both genetic and environmental components. Our prior genome scan in 511 affected sib-pairs and other relative pairs identified significant or suggestive linkage signals on chromosomes 1, 2, 3, 6, 8, 10, 12, 16, and 22. Purpose:To search for genetic loci for AMD using the extremely discordant sib-pair (EDSP) method of linkage analysis, which until now has never been applied to the study of AMD. Methods: The EDSP method is a more powerful approach than standard methods which rely on relative pairs selected at random or pairs concordant for the phenotype. The EDSP approach has also been characterized as the only design that is uniformly powerful in nearly all genetic situations. Thus, substantial reductions in sample size can be achieved. Study population:The study sample for analysis included 110 ...

A Discordant Sib-Pair Linkage Analysis of Age-Related Macular Degeneration

Autism spectrum disorders (ASD) are much more common in males than in females Studies using both linkage and candidate gene association approaches have identified genetic variants specific to families in which all affected cases were male, suggesting that sex may interact with or otherwise influence the expression of specific genes in association with ASD In this study, we specifically evaluated the sex-specific genetic effects of ASD with a family-based genome-wide association study approach using the data from the Autism Genetic Resource Exchange repository We evaluated the male-specific genetic effects of ASD in 374 multiplex families of European ancestry in which all affected were male (male-only; MO) and identified a novel genome-wide significant association in the pseudoautosomal boundary on chromosome Xp2233/Yp1131 in the MO families of predominantly paternal origin (rs2535443, p = 38 × 10−8) Five markers that reside within a 550 kb intergenic region on chromosome 13q333, between the MYO16 and IRS2 genes, also showed suggestive association with ASD in the MO families (p = 33 × 10−5 to 53 × 10−7) In contrast, none of these markers appeared to be associated with ASD in the families containing any affected females Our results suggest that the pseudoautosomal boundary on Xp2233/Yp1131 may harbor male-specific genetic variants for ASD © 2013 Wiley Periodicals, Inc

https://www.onlinelibrary.wiley.com/doi/pdf/10.1002/ajmg.b.32165

Sex-specific association of a common variant of the XG gene with autism spectrum disorders.

In 2015, two strong earthquakes, as well as continuous, high magnitude aftershocks, struck Nepal. Phulpingdanda village was greatly impacted due to its lack of infrastructure and environmental remoteness. Adults from sampled households were surveyed 1-year later to examine the association between earthquake exposures and indicators of depression, post-traumatic stress disorder (PTSD), and resilience. Results showed 33% of surveyed residents screened positive for depression, 9% screened positive for severe PTSD, and 46% displayed moderate to high resilience. Additionally, participants experienced resource loss (100%), damaged home and goods (99%), and exposure to the grotesque (82%). Traumatic earthquake experiences related to personal harm were associated with symptoms of depression and PTSD and resource loss was associated with depressive symptoms. Earthquake experiences associated with less damage to home and goods, but greater exposure to the grotesque were associated with increased resilience. This research adds to our knowledge of the relationship between traumatic exposures and indicators of psychological distress and resilience following a disaster.

Association between earthquake exposures and mental health outcomes in Phulpingdanda Village after the 2015 Nepal earthquakes.

Psychiatric hospitalization of children with autism spectrum disorder (ASD) is relatively common and occurs at a higher rate than in non-ASD youth. This study compared changes in the severity of serious problem behaviors in 350 youth with ASD enrolled in the autism inpatient collection during and after hospitalization in six specialized child psychiatry units. There was a significant reduction in serious problem behaviors from admission (aberrant behavior checklist—irritability subscale M = 29.7, SD 9.6) to discharge (M = 15.0, SD 10.3) and 2-month follow-up (M = 19.3, SD 10.3). Between discharge and 2-month follow-up, tantrum-like behaviors but not self-injurious behaviors increased slightly. Improvement in the severity of problem behaviors was not uniform across sites, even after controlling for measured site differences.

Susan L. Santangelo

Papers

A Discordant Sib–Pair Linkage Analysis of Age–Related Macular Degeneration

A Discordant Sib-Pair Linkage Analysis of Age-Related Macular Degeneration

Sex-specific association of a common variant of the XG gene with autism spectrum disorders.

Association between earthquake exposures and mental health outcomes in Phulpingdanda Village after the 2015 Nepal earthquakes.

Behavioral Outcomes of Specialized Psychiatric Hospitalization in the Autism Inpatient Collection (AIC): A Multisite Comparison