Version: iWES v3 2024_08 Assembly: Human Dec. 2013 (GRCh38/hg38)
Description
The Simons Foundation Autism Research
Initiative (SFARI) recruited a large cohort of families with autistic children who provided
DNA samples and phenotypes. 54,558 families, parents and their children were sequenced, a total
of 142,357 individuals with whole-exome (WES) and 12,519 with whole-genome sequencing (WGS).
The data contains 32,559 trios and 8,895 quads (one sibling without autism), and 824 twins.
The same frequencies shown here are also available publicly on the
SFARI Genome Browser.
See (SPARK et al, Neuron 2018) for details.
Phenotype-stratified counts
In addition to the overall allele count (AC), allele number (AN), and allele
frequency (AF), each variant record carries counts split by autism status
(the asd column of the SPARK individual registration file):
AC_AUT, AN_AUT, AF_AUT — individuals
coded as autistic (asd=TRUE).
AC_NON_AUT, AN_NON_AUT, AF_NON_AUT —
individuals coded as non-autistic (asd=FALSE); these are
mostly parents and unaffected siblings of the probands.
A small minority of samples have a blank asd value and so contribute
only to the overall AC/AN/AF, not to either group total.
Data Access
Due to license restrictions, the data for this track cannot be downloaded from the UCSC
Genome Browser. The Table Browser, Data Integrator, and download server are not available
for this track.
Allele frequencies can also be displayed on the
SFARI Genome Browser.
Full CRAMs and VCFs with genotypes are available from
SFARI Base.
They require a data access request, which is usually reviewed quickly. More information is
available in the
SPARK Welcome Packet.
Methods
The genome browser track project was approved by the Simons Foundation under request
number 14584.1. WES and WGS data were downloaded from
SFARI Base.
pVCFs were downloaded, anonymized with a script using bcftools and its "fill-tags" plugin and
normalized. There was no minimum allele frequency cutoff.
The ASD-status sample-group file derived from the SPARK individuals_registration
TSV was passed to fill-tags via its -S option, which adds the per-group
AC_AUT/AN_AUT/AF_AUT and AC_NON_AUT/AN_NON_AUT/AF_NON_AUT
tags alongside the overall AC/AN/AF.
The methods are documented as follows by SFARI:
WGS:
This release consists of sequence and variant call data for 12,519
unique individuals, of which 12,517 (99.98%) have available genome-wide
SNP genotype data. Sequencing and genotyping of all samples in this
release was performed at New York Genome Center (NYGC). DNA from saliva
samples were extracted and prepared with PCR-free methods and sequenced
with paired-end sequencing of 150 bases on the Illumina NovaSeq 6000
system. Alignment of reads to the human reference genome version
GRCh38, duplicate read marking, and Base Quality Score Recalibration
(BQSR) were performed by New York Genome Center (NYGC). Whole-genome
sequencing data were processed using a standardized, functionally
equivalent CCDG pipeline with alignment to the GRCh38DH (1000 Genomes)
reference using BWA-MEM v0.7.15 (deterministic settings, no -M, use of
.alt contigs), Picard-equivalent duplicate marking (Picard ≥2.4.1 or
equivalent), no indel realignment, and base quality score recalibration
with GATK (dbSNP138, Mills and 1000G gold-standard indels, known
indels). Final outputs were stored as lossless CRAM files with
complete SAM-compliant read-group annotations and mandatory 4-bin
base-quality compression (Q2—6, 10, 20, 30), and all implementations
were validated for functional equivalence across centers before use.
Variant Calling was performed using DeepVariant. See
CCDG pipeline details.
WES: This release contains
sequence data for 142,357 individuals and genotyping data for
141,368 individuals. DNA was sequenced from saliva for all
samples and all participants consented to having their genetic
data shared by Regeneron. Exomes for all samples were sequenced with
short-read, paired-end sequencing of 150 bases on Illumina
NovaSeq 6000 machines using S2/S4 flow cells. Sequencing and
genotyping was performed across nine batches (WES1 through
WES9) at the Regeneron Genetics Center (RGC) and integrated
together for this data release. All sequencing batches were
processed using the same DNA extraction methods and sequencing
machines, however two different exome capture panels were used,
as described below. Genotyping was performed using a SNP
genotyping array for WES1 through WES4 and using
"genotyping-by-sequencing" (GxS) for WES5 through WES9. The
first four sequencing batches were sequenced at Regeneron using
custom NEB/Kapa reagents with the IDT (Integrated DNA
Technologies) xGen capture platform, including custom exome
capture regions. Samples starting with batch WES5 were
sequenced using the Twist Bioscience Human
Comprehensive Exome panel, combined with spike-ins for
sequencing genotyping sites (see Genotyping Methods), the full
mitochondrial genome, and coverage boosted at selected sites
for assaying clonal hematopoiesis of indeterminate potential
(CHIP). SFARI performed SNV/indel calling via DeepVariant and
GATK to generate gVCFs, pairwise relatedness inferred using
PLINK v1.9 IBD estimates from common SNPs (AF ≥ 0.01, dbSNP
v151) with ≥15% relatedness flagged, and comprehensive
individual- and family-level quality control executed using the
internal GenomeCheckMate pipeline to exclude samples based on
contamination (≥5%), insufficient coverage (<20x in <80% of
targets), sex discordance, pedigree/IBD inconsistencies,
unregistered relationships, unexpected duplicates, or excess
relatedness, after which QC-passing individuals (selecting the
most recent passing sample per person) were retained for
variant calling and joint genotyping.
The makeDoc file documents how all source files of the varFreqs track were converted.
For some tracks, python scripts were necessary and are also available from GitHub.