Human gephyrin is encompassed within giant functional noncoding yin–yang sequences

Climer, Sharlee; Templeton, Alan R.; Zhang, Weixiong

doi:10.1038/ncomms7534

Cited by 14 publications

(6 citation statements)

References 69 publications

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“…This locus encodes a neuronal assembly protein that anchors glycine and GABAA receptors to the postsynaptic density in inhibitory neurons. 36 Intriguingly, the gephryin region exhibits an unusual ‘yin-yang' haplotype structure reflecting strong positive selection related to recent, rapid human evolution, 37 and has previously yielded suggestive evidence of association with depressive symptoms in the general population. 38 …”

Section: Resultsmentioning

confidence: 99%

Genetic effects influencing risk for major depressive disorder in China and Europe

et al. 2017

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Major depressive disorder (MDD) is a common, complex psychiatric disorder and a leading cause of disability worldwide. Despite twin studies indicating its modest heritability (~30–40%), extensive heterogeneity and a complex genetic architecture have complicated efforts to detect associated genetic risk variants. We combined single-nucleotide polymorphism (SNP) summary statistics from the CONVERGE and PGC studies of MDD, representing 10 502 Chinese (5282 cases and 5220 controls) and 18 663 European (9447 cases and 9215 controls) subjects. We determined the fraction of SNPs displaying consistent directions of effect, assessed the significance of polygenic risk scores and estimated the genetic correlation of MDD across ancestries. Subsequent trans-ancestry meta-analyses combined SNP-level evidence of association. Sign tests and polygenic score profiling weakly support an overlap of SNP effects between East Asian and European populations. We estimated the trans-ancestry genetic correlation of lifetime MDD as 0.33; female-only and recurrent MDD yielded estimates of 0.40 and 0.41, respectively. Common variants downstream of GPHN achieved genome-wide significance by Bayesian trans-ancestry meta-analysis (rs9323497; log10 Bayes Factor=8.08) but failed to replicate in an independent European sample (P=0.911). Gene-set enrichment analyses indicate enrichment of genes involved in neuronal development and axonal trafficking. We successfully demonstrate a partially shared polygenic basis of MDD in East Asian and European populations. Taken together, these findings support a complex etiology for MDD and possible population differences in predisposing genetic factors, with important implications for future genetic studies.

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Section: Resultsmentioning

confidence: 99%

Genetic effects influencing risk for major depressive disorder in China and Europe

et al. 2017

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“…GPHN encodes the scaffold protein gephyrin, which has been the subject of extensive study due to its central role in regulating the function of neurons, among the many other diverse functions of its splice variants (Ramming et al 2000;Lencz et al 2007;Tyagarajan and Fritschy 2014). GPHN has received attention as the candidate of a recent selective sweep ancestral to the human out-of-Africa migration event (Voight et al 2006;Williamson et al 2007;Park 2012), which has resulted in the maintenance of two high-frequency haplotypes worldwide (Climer et al 2015). Although not meeting the genome-wide significance threshold, we see that a large signal peak is centered over GPHN, and the underlying haplotype structure shows two high-frequency haplotypes at similar frequency in the pooled population and in the individual populations (Figure 6, top row).…”

Section: Specific Sweep Candidates Of Interest Across All Populationmentioning

confidence: 99%

Identifying and Classifying Shared Selective Sweeps from Multilocus Data

Harris

DeGiorgio

2020

Genetics

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Positive selection causes beneficial alleles to rise to high frequency, resulting in a selective sweep of the diversity surrounding the selected sites. Accordingly, the signature of a selective sweep in an ancestral population may still remain in its descendants. Identifying signatures of selection in the ancestor that are shared among its descendants is important to contextualize the timing of a sweep, but few methods exist for this purpose. We introduce the statistic SS-H12, which can identify genomic regions under shared positive selection across populations and is based on the theory of the expected haplotype homozygosity statistic H12, which detects recent hard and soft sweeps from the presence of high-frequency haplotypes. SS-H12 is distinct from comparable statistics because it requires a minimum of only two populations, and properly identifies and differentiates between independent convergent sweeps and true ancestral sweeps, with high power and robustness to a variety of demographic models. Furthermore, we can apply SS-H12 in conjunction with the ratio of statistics we term H2Tot and H1Tot to further classify identified shared sweeps as hard or soft. Finally, we identified both previously reported and novel shared sweep candidates from human whole-genome sequences. Previously reported candidates include the well-characterized ancestral sweeps at LCT and SLC24A5 in Indo-Europeans, as well as GPHN worldwide. Novel candidates include an ancestral sweep at RGS18 in sub-Saharan Africans involved in regulating the platelet response and implicated in sudden cardiac death, and a convergent sweep at C2CD5 between European and East Asian populations that may explain their different insulin responses.

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“…BlocBuster's unique features have enabled us to identify genetic patterns that have been previously overlooked, and revealed combinatorial genetic patterns with strong associations with hypertensive heart disease 21 and psoriasis 20 , as well as a coadaptation pattern between vitamin D receptor and skin color genes 22 . Furthermore, analysis of HapMap 23 data yielded the discovery of remarkable 'yin-yang' sequences 24 . Notably, the HapMap data are arguably the most extensively studied genome-wide data in existence, yet exhaustive studies using conventional methods failed to detect this genetic anomaly, demonstrating BlocBuster's distinctive power for the discovery of combinatorial patterns hidden in genetic data.…”

Section: Discussionmentioning

confidence: 99%

Synchronized genetic activities in Alzheimer’s brains revealed by heterogeneity-capturing network analysis

Climer

Templeton

Garvin

et al. 2020

Preprint

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It is becoming increasingly evident that the efficacy of single-gene computational analyses for complex traits is nearly exhausted and future advances hinge on unraveling the intricate combinatorial interactions among multiple genes. However, the discovery of modules of genes working in concert to manifest a complex trait has been crippled by combinatorial complexity, genetic heterogeneity, and validation biases. We introduce Maestro, a novel network approach that employs a multifaceted correlation measure, which captures heterogeneity, and a rigorous validation method. Maestro's utilization for Alzheimer's disease (AD) reveals an expression pattern that has virtually zero probability of simultaneous expression by an individual, assuming independence. Yet this pattern is exhibited by 19.0% of AD cases and 7.3% of controls, establishing an unprecedented pattern of synchronized genetic activities in the human brain. This pattern is significantly associated with AD, with an odds ratio of 3.0. This study substantiates Maestro's power for discovery of orchestrated genetic activities underlying complex traits. More generally, Maestro can be applied in diverse domains in which heterogeneity exists.

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Human gephyrin is encompassed within giant functional noncoding yin–yang sequences

Cited by 14 publications

References 69 publications

Genetic effects influencing risk for major depressive disorder in China and Europe

Genetic effects influencing risk for major depressive disorder in China and Europe

Identifying and Classifying Shared Selective Sweeps from Multilocus Data

Synchronized genetic activities in Alzheimer’s brains revealed by heterogeneity-capturing network analysis

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