Population genetics is central to our understanding of human variation, and by linking medical and evolutionary themes, it enables us to understand the origins and impacts of our genomic differences. Despite current limitations in our knowledge of the locations, sizes and mutational origins of structural variants, our characterization of their population genetics is developing apace, bringing new insights into recent human adaptation, genome biology and disease. We summarize recent dramatic advances, describe the diverse mutational origins of chromosomal rearrangements and argue that their complexity necessitates a re-evaluation of existing population genetic methods.

Population genetics of structural variation

INTRODUCTION MAPT H1 haplotype is implicated as a risk factor for neurodegenerative diseases including Alzheimer's disease (AD). METHODS Using Alzheimer's Disease Genetics Consortium (ADGC) genome-wide association study (GWAS) data (n = 18,841), we conducted a MAPT H1/H2 haplotype-stratified association to discover MAPT haplotype-specific AD risk loci. RESULTS We identified 11 loci-5 in H2-non-carriers and 6 in H2-carriers-although none of the MAPT haplotype-specific associations achieved genome-wide significance. The most significant H2 non-carrier-specific association was with a NECTIN2 intronic (P = 1.33E-07) variant, and that for H2 carriers was near NKX6-1 (P = 1.99E-06). The GABRG2 locus had the strongest epistasis with MAPT H1/H2 variant rs8070723 (P = 3.91E-06). Eight of the 12 genes at these loci had transcriptome-wide significant differential expression in AD versus control temporal cortex (q < 0.05). Six genes were members of the brain transcriptional co-expression network implicated in "synaptic transmission" (P = 9.85E-59), which is also enriched for neuronal genes (P = 1.0E-164), including MAPT. DISCUSSION This stratified GWAS identified loci that may confer AD risk in a MAPT haplotype-specific manner. This approach may preferentially enrich for neuronal genes implicated in synaptic transmission.

MAPT haplotype–stratified GWAS reveals differential association for AD risk variants

About 40-60% of patients with late-onset Alzheimer's disease (AD) develop psychosis, which represents a distinct phenotype of more severe cognitive and functional deficits. The estimated heritability of AD+P is ~61%, which makes it a good target for genetic mapping. We performed a genome-wide copy-number variation (CNV) study on 496 AD cases with psychosis (AD+P), 639 AD subjects with intermediate psychosis (AD intermediate P) and 156 AD subjects without psychosis (AD-P) who were recruited at the University of Pittsburgh Alzheimer's Disease Research Center using over 1 million single-nucleotide polymorphisms (SNPs) and CNV markers. CNV load analysis found no significant difference in total and average CNV length and CNV number in the AD+P or AD intermediate P groups compared with the AD-P group. Our analysis revealed a marginally significant lower number of duplication events in AD+P cases compared with AD-P controls (P=0.059) using multivariable regression model. The most interesting finding was the presence of a genome-wide significant duplication in the APC2 gene on chromosome 19, which was protective against developing AD+P (odds ratio=0.42; P=7.2E-10). We also observed suggestive associations of duplications with AD+P in the SET (P=1.95E-06), JAG2 (P=5.01E-07) and ZFPM1 (P=2.13E-07) genes and marginal association of a deletion in CNTLN (P=8.87E-04). We have identified potential novel loci for psychosis in Alzheimer's disease that warrant follow-up in large-scale independent studies.

/pdf/genome-wide-copy-number-variation-study-of-psychosis-in-52bdl2v49f.pdf

Genome-wide copy-number variation study of psychosis in Alzheimer's disease.

Psychotic symptoms, comprised of delusions and hallucinations, occur in about half of individuals with Alzheimer disease (AD with psychosis, AD+P). These individuals have greater agitation, aggression, depression, functional impairment, and mortality than individuals without psychosis (AD-P). Although the exact etiopathogenesis of AD+P is unclear, the rapidly developing field of genomics continues to expand our understanding of this disease. Several independent studies have demonstrated familial aggregation and heritability of AD+P. Linkage studies have been suggestive of loci on several chromosomes associated with AD+P. Association studies examining apolipoprotein E gene, the best established genetic risk factor for late-onset AD, did not find any significant association of this gene with AD+P. Other candidate gene studies focusing on monoamine neurotransmitter systems have yielded equivocal results. A genome-wide association study and studies examining copy number variations recently have detected suggestive associations, but have been underpowered. Approaches to increase sizes of AD+P samples for genome wide association studies are discussed. © 2016 Wiley Periodicals, Inc.

Genetics of psychosis of Alzheimer disease.

Adult-onset neuropsychiatric diseases are one of the most challenging areas of medicine. While symptomatic treatments are available, for most of these diseases the exact pathomechanism is not known, thus, disease-modifying therapies are difficult to conceptualize and find. The two most common and best studied neuropsychiatric diseases affecting higher cortical functions in humans are schizophrenia and Alzheimer's disease; both diseases have high heritability, however, the genetic architecture is not fully elucidated. Robust Single Nucleotide Variant (SNV) studies have identified several loci with modest effect sizes. While Copy Number Variants (CNV) make an important contribution to genetic variation, CNV GWAS suffer from dependence on mainly SNP arrays with underperforming genotyping accuracy. We evaluated dynamic range of the assays for three types of CNV loci, including biallelic deletion, high copy gain, and fusion gene, to assess the depth of exploration of the contribution of CNVs to disease susceptibility. Despite the suboptimal genotyping, novel mechanisms are emerging and further large-scale studies with genotyping assays optimized for CNV detection are needed. Furthermore, the CHRFAM7A human-specific fusion gene association warrants large scale locus specific association studies in AD, schizophrenia, bipolar disorder and ADHD.

/pdf/copy-number-variations-in-adult-onset-neuropsychiatric-2ugyb9kovh.pdf

Copy Number Variations in Adult-onset Neuropsychiatric Diseases.

Genetic heterogeneity is a common problem for genome-wide association studies of complex human diseases. Ordered-subset analysis (OSA) reduces genetic heterogeneity and optimizes the use of phenotypic information, thus improving power under some disease models. We hypothesized that in a genetically heterogeneous disorder such as Alzheimer's disease (AD), utilizing OSA by age at onset (AAO) of AD may increase the power to detect relevant loci. Using this approach, 8 loci were detected, including the chr15 : 30,44 region harboring CHRFAM7A. The association was replicated in the NIA-LOAD Familial Study dataset. CHRFAM7A is a dominant negative regulator of CHRNA7 function, the receptor that facilitates amyloid-β1-42 internalization through endocytosis and has been implicated in AD. OSA, using AAO as a quantitative trait, optimized power and detected replicable signals suggesting that AD is genetically heterogeneous between AAO subsets.

/pdf/ordered-subset-analysis-of-copy-number-variation-association-53s6ewbhto.pdf

Ordered subset analysis of copy number variation association with age at onset of Alzheimer's disease.

Biomarkers are emerging as important tools in the detection and monitoring of various diseases. A major limitation and challenge to effectively utilize biomarker signals is the limited understanding of factors contributing to their variance. As genetic variation is a major contributor to phenotypic variation, exploring genetic contributions is of great importance. Copy number variants (CNVs) offer an alternative genomic framework to understand contributions to phenotypic variance. A copy-number variation genome-wide association study was performed using 116 serum inflammatory biomarkers as quantitative trait in elderly normal controls to test the hypothesis that CNVs contribute to the phenotypic heterogeneity of serum biomarkers. Three chromosomal regions were associated with four biomarkers in trans. Transforming growth factor alpha (TG-alpha) serum levels were associated with CNV dosage at chr11:5,788 kb, soluble levels of receptor for advanced glycation endproducts (sRAGE) was associated with CNV dosage at chr8:40,183 kb and both thrombospondin-1 and tissue inhibitor of metalloproteinase 1 (TIMP-1) were associated with CNV dosage at chr11:18,961 kb. The CNV at chr11:5,788 kb harbors 2 olfactory genes and the introns of Tripartite motif-containing (TRIM) gene cluster TRIM5&22 while the CNV at chr11:18,961 includes the Mas-related G-protein coupled receptor member X1. These trans associations may identify novel relationships in the relevant pathways and suggest that genetic variation can contribute to biomarker levels. The detected trans-association between MRGPRX1 and thrombospondin-1/TIMP-1 could implicate a novel pathway between pain/itching and inflammation. Cataloguing all genetic variants with an effect on biomarkers will serve as a tool to interpret epidemiological studies and establish causal relationships through Mendelian randomization.

https://journals.sagepub.com/doi/pdf/10.1177/1721727X1401200206

Genome-Wide Scan for Copy Number Variation Association with Biomarker Quantitative Trait Loci in Aging

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Ordered subset analysis of copy number variation association with age at onset of Alzheimer's disease.

Genome-Wide Scan for Copy Number Variation Association with Biomarker Quantitative Trait Loci in Aging