Table 5.

Main whole exome sequencing/whole genome sequencing (WES/WGS) findings in major psychiatric disorders.

Diseases	Technology	Study Design	Sample Size	Project	Finding	Year	Reference
ASD	WES	Case-control	3871 ASD cases and 9937 controls (15,480 DNA samples)	Autism Sequencing Consortium (ASC)	33 ASD risk genes, and rare coding variations enriched in 107 genes implicated in synaptic, transcriptional, and chromatin remodeling pathways; de novo loss-of-function mutations in over 5% of autistic subjects.	2014	[166]
ASD	WES	Family study	2517 families (2508 probands, 1911 siblings, 5034 parents)	Simons Simplex Collection (SSC)	27 ASD associated genes; 13% of de novo (DN) missense mutations and 42% of DN likely gene-disrupting (LGD) mutations contributed to 12% and 9% of diagnoses, respectively. Including copy number variants, coding DN mutations contribute to about 30% of all simplex and 45% of female diagnoses.	2014	[167]
ASD	SNP chip and WES	Family study	2591 families (10,220 individuals)	SSC, ASC	Small de novo deletions overlaps high effect with de novo loss of function; Identified 71 ASD risk loci, including 6 CNV regions and 65 risk genes.	2015	[168]
ASD	WES	Family study	5947 families (4032 trios, 1918 quads)	SSC, ASC	Identified 7.5% of de novo mutations as postzygotic mosaic mutations (PZMs); Damaging, nonsynonymous PZMs within critical exons of prenatally expressed genes were more common in ASD probands than controls (p < 1 × 10−6), and genes carrying these PZMs were enriched for expression in the amygdala (p = 5.4 × 10−3).	2017	[169]
SCZ	WES	Case-control	2536 SCZ and 2543 controls	Swedish SCZ case-control study via Hospital Discharge Register	Polygenic burden of SCZ primarily arising from rare disruptive mutations distributed across many genes and enrichment in the voltage-gated calcium ion channel and the signaling complex formed by the activity-regulated cytoskeleton-associated (ARC) scaffold protein of the postsynaptic density (PSD).	2014	[170]
SCZ	WES	Combined family and case-control study	4264 cases, 9343 controls and 1077 trios	UK10K schizophrenia analysis (UK, Finnish), Swedish schizophrenia case-control study	Histone H3K4 methylation pathway is associated with SCZ; Genome-wide significant association between rare loss-of-function (LoF) variants in SETD1A and risk for schizophrenia (p = 3.3 × 10−9).	2016	[171]
SCZ	WES	Case-control	4946 SCZ, 6242 controls, and 1144 with other psychiatric illnesses	Swedish SCZ case-control study via Hospital Discharge Register	Ultra rare gene-disruptive and putatively protein-damaging variants were more abundant in schizophrenia cases than controls (p = 1.3 × 10−10).	2016	[172]
SCZ	WES	Meta-analysis for combined SNVs and CNVs	4133 SCZ and 9274 controls (4,133 SCZ and 9274 controls AND 1077 trios; 6882 cases and 11,255 controls using CNVs)	UK10K, INTERVAL, Finnish SCZ STUDY, Swedish SCZ Study	Rare, damaging variants contribute to the risk of schizophrenia both with and without intellectual disability; and support an overlap of genetic risk between schizophrenia and other neurodevelopmental disorders.	2017	[173]
BPD	WES	Combined family and case-control study	8 families (36 BPD), independent case-control samples consisting of 3541 BPD cases and 4774 controls	Swedish Exome Sequencing Study; BRIDGES	84 rare (frequency < 1%), damaging variants segregating within families; the case-control meta-analyses yielded 19 genes that were nominally associated with BPD; overlap of potential risk genes with autism and schizophrenia.	2016	[174]
BPD	WES		4 families (15 individuals)	NIMH Bipolar Genetics Initiativee	14 variants in 14 genes were associated with bipolar disorder when tested against 2545 unaffected controls and 2543 patients with schizophrenia (p < 0.05 after Bonferroni correction).	2017	[175]
MDD	WES	Combined family and case-control linkage and association studies	Discovery cohort: 2393 individuals; Replication cohort: 1604 individuals	Discovery: the Erasmus Rucphen Family (ERF) study for depressive symptoms; Replication: Rotterdam Study for depressive symptoms	Missense c.1114C >T mutation (rs115482041) in the RCL1 gene segregating with depression across multiple generations. Rs115482041 showed significant association with depressive symptoms (N = 2393, βT-allele = 2.33, p-value = 1 × 10−4) and explained 2.9% of the estimated genetic variance of depressive symptoms (22%) in ERF; and significant association with depressive symptoms in samples from the independent population-based Rotterdam study (N = 1604, βT-allele = 3.60, p-value = 3 × 10−2).	2017	[176]
MDD	WES	Combined family and case-control study	Discovery cohort: 1265 individuals Replication cohort: 3612 individuals	Discovery cohort: Rotterdam Study for depressive symptoms; Replication cohort: Erasmus Rucphen Family (ERF) study	A missense Asn396Ser mutation (rs77960347) in the endothelial lipase (LIPG) gene, occurring with an allele frequency of 1% in the general population, which was significantly associated with depressive symptoms (p-value = 5.2 × 10−8, β = 7.2). Replication in three independent data sets (N = 3612) confirmed the association of Asn396Ser (p-value = 7.1 × 10−3, β = 2.55) with depressive symptoms.	2017	[177]
MDD	WES	Combined family and case-control study	Discovery: 1999 individuals; Replication: 2356 individuals	Discovery: the Erasmus Rucphen Family (ERF) study for depressive symptoms; Replication: Rotterdam Study for depressive symptoms	Rare nonsynonymous variants in NKPD1 is associated with depressive symptoms in discovery cohort (p = 3.7 × 10−8); variants explained 0.9% of the age- and sex-adjusted variance and 3.8% of heritability of depressive symptoms in the ERF population; meta-analysis of the discovery and replication studies improved the association signal (p = 1.0 × 10−9).	2017	[178]
ASD	WGS	Family study	2626 ASD cases and 2579 family controls	AGRE, autism Treatment Network, Genomes to Outcomes Study; Baby Siblings Research Consortium, The Autism Simplex Collection, Infant Sibling Study, Pathways in ASD	An average of 73.8 de novo SNVs and 12.6 de novo insertions and deletions or CNVs per ASD subject; 18 new candidate ASD-risk genes were identified. In 294 of 2620 (11.2%) of ASD cases, a molecular basis could be determined and 7.2% of these carried copy number variations and/or chromosomal abnormalities, emphasizing the importance of detecting all forms of genetic variation as diagnostic and therapeutic targets in ASD.	2017	[179]
BPD	WGS	Family study	41 families (200 individuals) and 254 individuals as controls	NIMH	An increased burden of rare variants in genes encoding neuronal ion channels, including subunits of GABAA receptors and voltage-gated calcium channels; most of the risk variants in noncoding predicted regulatory effects.	2015	[180]
SCZ	WGS	Family study	9 multiplex families (90 individuals)	Coriell Institute in Camden	In one family, seven siblings with schizophrenia spectrum disorders each carry a novel private missense variant within the SHANK2 gene. In another family, four affected siblings and their unaffected mother each carry a novel private missense variant in the SMARCA1 gene on the X chromosome.	2016	[181]
MDD	WGS	Case-control, low coverage WGS	Discovery: 5303 cases, 5337 controls (Chinese women); Replication cohort 1: a separate Han Chinese cohort of 3231 cases with recurrent MDD, and 3186 controls; Replication cohort 2: 9240 European MDD cases and 9519 controls	CONVERGE Consortium	Two genome-wide significant loci contributing to risk of MDD on chromosome 10: SIRT1 gene (p = 2.53 × 10−10) and LHPP gene (p = 6.45 × 10−12); common SNPs explained between 20% and 29% of the variance in MDD risk; support a substantial polygenic component to the risk of MDD involving many alleles of individually very small effect; the MDD risk allele frequencies of rs12415800 and rs35936514 are different according to ethnicity, confirmed in Chinese replication cohort but failed in European MDD cohorts. Results support a complex etiology for MDD.	2015–2017	[182,183,184,185]